A beta-adrenergic agonist that stimulates predominantly beta-adrenergic receptors. It has a bronchodilator (dilates the lumen of the bronchi) effect. Inhibits (suppresses) the release of histamine and leukotrienes (biologically active substances produced in the body) from lung tissue. The onset of action of the drug is after 5 minutes, maximum after 2 hours, the duration of action in case of reversible broncho-obstruction (impaired air flow through the bronchi) is up to 10 hours.

Indications for use:

Prevention and treatment of bronchospasm (sharp narrowing of the lumen of the bronchi) in patients with obstructive bronchitis (inflammation of the bronchi, combined with impaired air flow through them); bronchial asthma; bronchospasm caused by an allergen or physical activity.

Mode of application:

The drug is administered by inhalation. To relieve (relieve) acute bronchospasm, you should take a single inhalation (12 mcg) of the drug, and if necessary, inhale again after a minute. Maximum daily dose 96 mcg (8 puffs). To prevent asthma attacks, administer 12 mcg (1 breath) 2 times a day after 12 hours, severe cases- 24 mcg 2 times a day at least every 8 hours.

Side effects:

Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (rapid heartbeat), nausea.

Contraindications:

Pregnancy, breastfeeding, increased sensitivity to the drug or beta-agonists. When using the drug, patients are not recommended to engage in activities that require increased attention or coordination of movements. Formoterol should not be combined with other adrenergic agonists, MAO inhibitors, or tricyclic antidepressants. The drug is prescribed with caution to patients suffering from diabetes mellitus, and with fibroids (benign tumors of the muscular layer) of the uterus.

Release form:

Metered aerosol for inhalation in an inhaler, 100 doses. One dose contains 12 mcg of formoterol fumarate.

Storage conditions:

List B. In a cool place, avoid freezing. Protect from direct sun rays and heat sources. Synonyms: Foradil. Attention! Before using the drug Formoterol, you should consult your doctor. This instruction is given in free translation and is intended for informational purposes only. To get more complete information Please refer to the manufacturer's instructions. Formoterol

Latin name

Formoterol

Chemical name

(R*,R*)-(±)-N-amino]ethyl]phenyl]formamide (as fumarate)

Gross formula

C19H24N2O4

Pharmacological group

Beta-agonists

Nosological classification (ICD-10)

J42 Chronic bronchitis, unspecified
J43 Emphysema
J44 Other chronic obstructive pulmonary disease
J45 Asthma
J98.8.0* Bronchospasm

CAS Code

73573-87-2

Characteristic

Available in the form of formoterol fumarate and formoterol fumarate dihydrate. Formoterol fumarate is a white or yellowish crystalline powder. Easily soluble in ice acetic acid, soluble in methanol, to a lesser extent in ethanol and isopropanol, slightly soluble in water, practically insoluble in acetone, ethyl acetate and diethyl ether. Molecular weight 840.9.

Pharmacology

Pharmacological action: adrenomimetic, bronchodilator.

Formoterol fumarate is a long-acting selective adrenergic beta 2 receptor agonist. When inhaled, formoterol fumarate acts locally on the bronchi, causing bronchodilation. In vitro studies have shown that its activity against beta 2 adrenergic receptors, located mainly in the smooth muscles of the bronchi, is more than 200 times higher than that against beta 1 adrenergic receptors, located mainly in the myocardium. Beta 2 adrenergic receptors are also found in the myocardium, constituting up to 10-50% of the total number of beta adrenergic receptors. The exact function of these receptors has not been established, but they increase the potential for cardiac effects of even highly selective beta 2-agonists. Formoterol fumarate stimulates intracellular adenylate cyclase, which catalyzes the transformation of ATP into cAMP. An increase in cAMP levels causes relaxation of bronchial smooth muscle and inhibits the release of immediate hypersensitivity mediators from cells, especially from mast cells. In vitro studies have shown that formoterol fumarate inhibits the release of mediators (histamine and leukotrienes) from mast cells in the human lung. In animal studies, formoterol fumarate was found to inhibit histamine-induced extravasation of plasma albumin in guinea pigs anesthetized patients and allergen-induced eosinophil influx in dogs with airway hyperresponsiveness. The significance of these findings from animal and in vitro studies is unclear in humans.

The main side effects of inhaled beta 2 -adrenergic agonists are the result of excessive activation of systemic beta adrenergic receptors. The most common side effects in adults and adolescents include skeletal muscle tremors and seizures, insomnia, tachycardia, hypokalemia and hyperglycemia.

The pharmacokinetic and pharmacodynamic relationships between heart rate, ECG parameters, plasma potassium levels and renal excretion of formoterol fumarate were studied in 10 healthy male volunteers aged 25 to 45 years after a single inhalation of 12, 24, 48 or 96 mcg of formoterol fumarate. A linear relationship was found between renal excretion of formoterol fumarate and a decrease in plasma potassium, an increase in plasma glucose and an increase in heart rate. In another study, 12 volunteers received a single dose of 120 mcg of formoterol fumarate (10 times the recommended single dose). In all subjects, the potassium content in the blood plasma decreased as much as possible by 0.55-1.52 mmol/l (the average maximum decrease was 1.01 mmol/l). A strong correlation was noted between the concentration of formoterol fumarate and the potassium content in the blood plasma: greatest influence on potassium levels was observed 1-3 hours after reaching the Cmax of formoterol fumarate. On average, the maximum increase in heart rate was observed 6 hours after taking formoterol fumarate and was 26 beats per minute. The maximum prolongation of the corrected QT interval (QTc) when calculated using the Bazett formula averaged 25 milliseconds, and according to the Fredericia formula - 8 milliseconds. The QTc interval returned to baseline 12-24 hours after taking formoterol fumarate. Plasma formoterol concentrations were weakly correlated with heart rate and QTc increase. Effects on plasma potassium levels, pulse rate, QTc interval - known pharmacological effects class of drugs to which formoterol fumarate belongs, so their appearance in the study is very high doses formoterol fumarate (120 mcg single dose, 10 times the recommended single dose) was not unexpected. These phenomena were well tolerated by healthy volunteers.

The electrocardiographic and cardiovascular effects of formoterol fumarate were compared with the effects of albuterol (not registered in Russia) and placebo in two 12-week double-blind studies in patients with bronchial asthma; The studies involved long-term ECG monitoring over three 24-hour periods. There were no significant differences in ventricular or supraventricular ectopia between patient groups (in these two studies, the total number of patients with bronchial asthma who received any dose of formoterol fumarate and underwent long-term ECG monitoring was about 200 people). The effect of formoterol fumarate compared with placebo on the ECG of patients with chronic obstructive pulmonary disease (COPD) was assessed in a 12-month study (without long-term ECG monitoring). ECG interval analysis was performed on patients participating in US studies; of these, 46 people took formoterol fumarate 12 mcg 2 times a day and 50 patients took 24 mcg twice a day. ECG was recorded before use and 5-15 minutes and 2 hours after the first use of the drug, then after 3, 6 and 12 months of treatment. According to the results of the study, clinically significant acute or chronic influence for ECG intervals, incl. QTc was not detected during treatment with formoterol fumarate. Formoterol fumarate, like other beta-agonists, can cause flattening of the T wave and ST segment depression on the ECG; clinical significance these changes are unknown.

Tolerance. During clinical studies on 19 adult patients with bronchial asthma moderate severity The bronchoprotective effect of formoterol fumarate was assessed by the response in a test with methacholine after taking an initial dose of 24 mcg (twice the recommended dose) and 2 weeks later when taking 24 mcg twice a day. Tolerance to the bronchoprotective effect of formoterol fumarate, as evidenced by a decrease in the bronchoprotective effect in relation to forced expiratory volume in 1 s (FEV 1), was observed after 2 weeks of taking the drug, loss protective properties observed at the end of the 12-hour period after administration. No rebound bronchial hyperreactivity reactions were observed after discontinuation of long-term therapy with formoterol fumarate.

Clinical researches

Studies in patients with bronchial asthma. In three big clinical studies In patients with bronchial asthma, while the effectiveness of formoterol fumarate was maintained compared with placebo, there was a slight decrease in the bronchodilatory response assessed within 12 hours, while the effect of formoterol fumarate remained unchanged, especially when taking 24 mcg twice daily (twice the recommended daily dose ).

In studies with single and multiple doses of formoterol fumarate at a dose of 12 mcg, the maximum improvement in FEV 1 was usually observed between 1 and 3 hours after dosing. An increase in FEV 1 compared to the initial value was detected within 12 hours after administration of the drug in most patients.

Two 12-week multicenter, randomized, comparative, double-blind, placebo studies in adults and adolescents 12 years of age and older with moderate to severe asthma (FEV 1 was 40-80% of normal values) showed that formoterol fumarate ( 12 mcg twice a day) not only caused significant bronchodilation, assessed by FEV 1, but also improved many secondary efficacy indicators, including improvements in combined and nocturnal asthma symptom scales, as well as a decrease in the number of night awakenings and nights when patients used drugs emergency care, an increase in morning and evening peak flow measurements (air flow speed).

Clinical studies in children. A 12-month, multicenter, randomized, double-blind, parallel-group study of formoterol fumarate and placebo included 518 children 5–12 years of age with asthma who required daily bronchodilators and anti-inflammatory drugs. The effectiveness of therapy was assessed on the first day, on the 12th week and at the end of the course of treatment; According to the study results, the 12-hour effectiveness of formoterol fumarate (as measured by FEV 1) exceeded that of the placebo group at all specified times.

Clinical studies of the effectiveness of formoterol fumarate in exercise-induced bronchospasm (the effect was assessed as a decrease in FEV 1 by more than 20%). Four randomized, double-blind comparative studies included 77 patients aged 4 to 41 years. The response to exercise was assessed by FEV 1 after 15 minutes, 4, 8 and 12 hours after a single dose of 12 μg of formoterol fumarate and placebo. The indicators in the formoterol fumarate group were significantly higher than those in the placebo group at all follow-up periods. The effectiveness of regular twice-daily use of formoterol in preventing exercise-induced asthma attacks has not been studied.

Clinical studies in patients with COPD. IN clinical trials with repeated administration of formoterol fumarate at a dose of 12 mcg, patients with COPD noted pronounced bronchodilation (increase in FEV 1 by 15% or more) 5 minutes after inhalation of the initial dose, lasting for 12 hours. According to two comparative studies Using placebo, formoterol fumarate (12 mcg) improved morning peak flow measurements compared with the pre-treatment period.

Pharmacokinetics

The pharmacokinetics of formoterol fumarate were studied in healthy volunteers who used it in doses exceeding the recommended ones, and in patients with COPD who received formoterol fumarate in therapeutic and higher doses. Urinary excretion of unchanged formoterol was used as an indirect indicator of systemic exposure. The distribution of formoterol from blood plasma corresponded to renal excretion, and T1/2 of distribution and elimination were similar. After a single inhalation of 120 mcg of formoterol fumarate in 12 healthy volunteers, it was rapidly absorbed into the plasma, reaching C max (92 pg/ml) within 5 minutes. In patients with COPD who received formoterol fumarate at a dose of 12 or 24 mcg twice daily for 12 weeks, its mean plasma concentration ranged from 4.0-8.8 pg/ml and 8.0-17.3 pg/ml. ml, respectively, 10 minutes, 2 and 6 hours after inhalation. After inhalation of 12-96 mcg of formoterol fumarate by 10 healthy volunteers, the urinary excretion of the R,R- and S,S-enantiomers of formoterol increased proportionally to the dose, i.e., the absorption of formoterol fumarate after inhalation is linear over the dose range considered.

In a study in patients with bronchial asthma who received 12 and 24 mcg of formoterol fumarate inhaled twice a day for 4 or 12 weeks, the accumulation index, assessed by excretion of unchanged drug in urine, ranged from 1.63-2.08 compared with initial dose. For patients with COPD who used formoterol fumarate 12 and 24 mcg twice daily for 12 weeks, the accumulation index, calculated from the excretion of unchanged drug in urine, was 1.19-1.38. This confirms some accumulation of formoterol fumarate in plasma with repeated dosing. The amount of formoterol fumarate eliminated at steady state was almost equal to that predicted based on pharmacokinetics after a single dose. Presumably most of formoterol fumarate (similar to other inhaled drugs) will be swallowed and then absorbed from the gastrointestinal tract. In vitro binding to plasma proteins is 61-64% at a concentration of 0.1-100 ng/ml, with albumin - 31-38% at a plasma concentration of 5-500 ng/ml (these plasma concentrations exceed those after inhalation of 120 mg formoterol fumarate). Formoterol fumarate is metabolized primarily by direct glucuronidation at a phenolic or aliphatic hydroxyl group and O-demethylation followed by conjugation with a glucuronide at any phenolic hydroxyl group. Another biotransformation pathway involves sulfation and deformylation, accompanied by sulfation. The predominant route is direct conjugation at the phenolic hydroxyl group, the second most important route is O-demethylation, accompanied by conjugation at the phenolic 2"-hydroxyl group. Four isoenzymes of cytochrome P450 (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol fumarate. At therapeutic concentrations, formoterol does not inhibit cytochrome P450 enzymes. In some patients, insufficient functional activity of one or both isoenzymes CYP2D6 and CYP2C19 may occur. However, could a deficiency of one or both isoenzymes lead to increased systemic exposure or the development of systemic side effects, unknown (no adequate studies have been conducted). Following oral administration of 80 mcg of radiolabeled formoterol fumarate to two healthy volunteers, 59-62% was excreted in urine and 32-34% in feces within 104 hours; their renal clearance of formoterol fumarate was about 150 ml/min. In 16 patients with bronchial asthma who received 12 mcg or 24 mcg of formoterol fumarate by inhalation, about 10% of the drug was excreted in the urine unchanged and 15-18% in the form of conjugates. In 18 patients with COPD who received formoterol fumarate in the same doses, these figures were 7% and 6-9%, respectively. After a single inhalation of 120 mcg of formoterol fumarate in 12 healthy volunteers, the terminal T1/2 (based on plasma concentration measurements) was 10 hours. When calculated based on the level of renal excretion, the terminal T1/2 for the R,R- and S,S-enantiomers of formoterol fumarate was 13.9 and 12.3 hours, respectively. After a single inhalation of 12-120 mcg of formoterol fumarate by healthy volunteers, a single and repeated dose of formoterol fumarate at a dose of 12 mcg or 24 mcg in patients with bronchial asthma, the proportion of R, R- and S, S-enantiomers of the unchanged substance found in the urine was 40% and 60%, respectively (the ratio of the two enantiomers remains constant over the dose range studied and there is no evidence of accumulation of one of them relative to the other with repeated doses).

After correction for body weight, there were no significant differences in pharmacokinetic parameters depending on gender. In clinical trials, formoterol fumarate was administered to elderly patients with asthma (318 people aged 65 years and older, 39 people aged 75 years and older) and COPD (395 and 62 people aged 65 years and older and 75 years and older, respectively) . Marked differences in the safety and effectiveness of formoterol fumarate in elderly and older people young was not identified; Respiratory tract infections were observed with a slightly higher frequency in patients aged 75 years and older, but their relationship with formoterol fumarate was not established. In children 5-12 years old with bronchial asthma who received inhaled formoterol fumarate at a dose of 12 mcg or 24 mcg twice a day for 12 weeks, the accumulation index, calculated from the renal excretion of unchanged formoterol fumarate, ranged from 1.18 to 1.84 (in adults - 1.63-2.08). About 6% of formoterol fumarate in unchanged form and 6.5-9% in the form of conjugates were found in the urine of children. The pharmacokinetics of formoterol fumarate in people with liver or kidney damage and in elderly patients has not been studied.

Experimental pharmacology

In animal studies (mini pigs, rodents, dogs), cases of arrhythmias and sudden death with histologically confirmed myocardial necrosis with simultaneous use of beta-adrenergic agonists and methylxanthine derivatives. The clinical significance of these facts for humans has not been determined.

Carcinogenicity, mutagenicity, effect on fertility

A study of the carcinogenicity of formoterol fumarate was carried out on rats and mice receiving it for 2 years with food or drinking water. In rats, the incidence of ovarian leiomyomas increased at doses of formoterol fumarate of 15 mg/kg or more in drinking water and 20 mg/kg in food. When 5 mg/kg formoterol fumarate (approximately 450 times the AUC of human exposure from inhaled MRDC) was administered in food, the incidence of ovarian leiomyoma in rats was not increased. The incidence of benign theca cell tumors of the ovary was increased when formoterol fumarate was taken with food at a dose equal to or greater than 0.5 mg/kg (AUC exposure of a dose of 0.5 mg/kg is approximately 45 times higher than the exposure of inhaled MRDC). These findings were not observed when formoterol fumarate was administered to rats through drinking water or in tests in mice. In male mice, the incidence of subcapsular adenomas and adrenal carcinomas increased when receiving 69 mg/kg or more of formoterol fumarate in drinking water; the development of these tumors was not observed when formoterol fumarate was taken with food in doses of about 50 mg/kg (AUC exposure is approximately 590 times higher than the exposure in humans when taken by inhalation of the maximum recommended daily dose). The development of hepatocarcinomas in mice was observed when 20 and 50 mg/kg of formoterol fumarate (females) and 50 mg/kg (males) were taken with food. The development of uterine leiomyomas and leiomyosarcomas has been observed when formoterol fumarate was taken with food in doses of 2 mg/kg or more (AUC exposure at a dose of 2 mg/kg is approximately 25 times higher than the exposure in humans after inhalation of the maximum recommended daily dose). Increased incidence of organ leiomyomas reproductive system in female rodents was similar to data from studies of other beta-agonists.

Formoterol fumarate did not exhibit mutagenic or clastogenic properties in the following tests: mutagenicity study on bacterial and mammalian cells, chromosomal analysis on mammalian cells, DNA repair study on rat hepatocytes and human fibroblasts, analysis of transformation of mammalian fibroblasts and micronucleus tests on mice and rats.

In a reproduction study in rats treated with oral formoterol fumarate at doses of approximately 3 mg/kg (approximately 1000 times the maximum recommended daily inhalation dose for humans based on body surface area in mg/m2), no impairment of fertility was observed. In rats treated with formoterol fumarate at a dose of 6 mg/kg (2000 times the maximum recommended daily inhalation dose for humans based on body surface area in mg/m2) later pregnancy, prenatal and neonatal mortality increased. These effects were not observed with formoterol fumarate at a dose of 0.2 mg/kg (70 times the maximum recommended daily inhalation dose for humans based on body surface area in mg/m2). A slowdown in skeletal ossification and a decrease in body weight were observed in fetuses of rats that received formoterol fumarate at a rate of 0.2 mg/kg and 6 mg/kg, respectively, during the period of organogenesis. In studies in rats and rabbits, formoterol fumarate did not cause malformations.

Application

According to the Physician Desk Reference (2009), formoterol fumarate is indicated for long-term (twice daily - morning and evening) maintenance therapy for bronchial asthma and prevention (in adults and children 5 years of age and older) of bronchospasm in reversible obstructive airway diseases, incl. in patients with symptoms of nocturnal asthma.

The use of formoterol fumarate "on demand" (if necessary) is indicated for adults and children 5 years of age and older for the rapid prevention of bronchospasm caused by exercise.

Formoterol fumarate is used for long-term (twice daily - morning and evening) maintenance therapy in patients with COPD, including chronic bronchitis and emphysema.

Contraindications

Hypersensitivity.

Restrictions on use

Cardiovascular disorders, incl. coronary insufficiency, arrhythmias, arterial hypertension, seizure disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breast-feeding, age up to 5 years (safety and effectiveness have not been established).

Formoterol fumarate is not recommended for patients whose bronchial asthma can be controlled only by non-systematic inhalation of short-acting beta 2 -adrenergic agonists, as well as for patients for whom therapy with inhaled corticosteroids or other drugs, one of which is occasionally inhaled short-acting beta 2 - is completely adequate. adrenomimetic.

Use during pregnancy and breastfeeding

Adequate controlled studies of formoterol fumarate in pregnant women, incl. during childbirth, was not carried out. Formoterol fumarate should be used during pregnancy and childbirth (as beta-agonists may adversely affect uterine contractility) only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Formoterol fumarate is excreted in rat milk. It is not known whether it is excreted in breast milk in women, but since many drugs are excreted in human milk, Formoterol fumarate should be administered with caution to nursing women (well-controlled studies have not been conducted in breastfeeding women).

Side effects

Side effects of formoterol fumarate are similar to the side effects of other selective beta 2 -agonists and include angina pectoris, arterial hypo- or hypertension, tachycardia, arrhythmia, nervousness, headache, tremor, dry mouth, palpitations, dizziness, convulsions, nausea, fatigue, weakness , hypokalemia, hyperglycemia, metabolic acidosis and insomnia.

Bronchial asthma

During controlled clinical trials, formoterol fumarate (12 mcg 2 times a day) was administered to 1985 patients (children 5 years and older, adolescents and adults) with bronchial asthma. Among the identified side effects of formoterol fumarate with a frequency of 1% or more, exceeding the frequency side effects in the placebo group, the following were noted (next to the name is the percentage of occurrence of this side effect in the formoterol fumarate group, in parentheses - in the placebo group):

From the outside nervous system and sensory organs: tremor 1.9% (0.4%), dizziness 1.6% (1.5%), insomnia 1.5% (0.8%).

From the outside respiratory system: bronchitis 4.6% (4.3%), organ infections chest 2.7% (0.4%), dyspnea 2.1% (1.7%), tonsillitis 1.2% (0.7%), dysphonia 1.0% (0.9%).

Others: viral infections 17.2% (17.1%), chest pain 1.9% (1.3%), rash 1.1% (0.7%).

Three side effects—tremor, dizziness, and dysphonia—were dose-dependent (doses of 6, 12, and 24 mcg administered twice daily were studied).

The safety of formoterol fumarate compared with placebo was studied in a multicenter, randomized, double-blind clinical trial in 518 children aged 5-12 years with asthma who required daily bronchodilators and anti-inflammatory drugs. When taking 12 mcg of formoterol fumarate 2 times a day, the frequency of side effects was comparable to that in the placebo group. The nature of the side effects detected in children differed from the side effects of formoterol fumarate noted in adults. Side effects in the formoterol fumarate group in children, which exceeded the frequency of detection side effect in the placebo group, included infections/inflammation (viral infections, rhinitis, tonsillitis, gastroenteritis) or gastrointestinal complaints (abdominal pain, nausea, dyspepsia).

In two controlled studies, 405 patients with COPD received formoterol fumarate (12 mcg twice daily). The incidence of adverse events was comparable in the formoterol fumarate and placebo groups. Among the side effects in the formoterol fumarate group with a frequency equal to or exceeding 1% and exceeding that in the placebo group, the following were noted (next to the name is the percentage of occurrence in the formoterol fumarate group, in parentheses - in the placebo group):

From the nervous system and sensory organs: convulsions 1.7% (0%), convulsions calf muscles 1.7% (0.5%), anxiety 1.5% (1.2%).

From the respiratory system: upper respiratory tract infections 7.4% (5.7%), pharyngitis 3.5% (2.4%), sinusitis 2.7% (1.7%), increased sputum 1.5 % (1.2%).

Other: back pain 4.2% (4.0%), chest pain 3.2% (2.1%), fever 2.2% (1.4%), itching 1.5% (1. 0%), dry mouth 1.2% (1.0%), trauma 1.2% (0%).

Overall, the incidence of all cardiovascular adverse events in the two main studies was low and comparable to placebo (6.4% in patients taking formoterol fumarate 12 mcg twice daily and 6.0% in the placebo group). No specific cardiovascular side effects were observed in the formoterol fumarate group, which occurred with a frequency of 1% or more and exceeded the frequency of occurrence in the placebo group.

In two studies in patients taking 12 mcg and 24 mcg of formoterol fumarate twice daily, seven side effects (pharyngitis, fever, convulsions, increased sputum production, dysphonia, myalgia and tremor) were noted to be dose-dependent.

Post-marketing studies

During widespread post-marketing use of formoterol fumarate, there were reports of severe exacerbations of asthma, some of which were fatal. Although most of these cases were observed in patients with severe bronchial asthma or acute decompensation of the condition, a few cases were observed in patients with less severe bronchial asthma. The relationship of these cases to the use of formoterol fumarate has not been determined. There are rare reports of anaphylactic reactions, including severe arterial hypotension and angioedema associated with inhaled formoterol fumarate. Allergic reactions may manifest as urticaria and bronchospasm. There was no evidence of the development of drug dependence with the use of formoterol fumarate in clinical trials.

Interaction

Other adrenergic agents should be used with caution while taking formoterol, as there is a risk of potentiating the predictable sympathomimetic effects of formoterol. At simultaneous administration xanthine derivatives, steroids or diuretics may enhance the hypokalemic effect of adrenergic receptor agonists. ECG changes and/or hypokalemia caused by non-potassium sparing diuretics, such as loop or thiazide diuretics, may be suddenly exacerbated by beta-agonists, especially when the dose is exceeded (although the clinical significance of these effects is unclear, caution is required when co-prescribing drugs of these groups ). Formoterol, like other beta 2 agonists, should be special attention prescribed while taking MAO inhibitors, tricyclic antidepressants or other medicines, capable of prolonging the QTc interval, as this may potentiate the effect of adrenergic agonists on cardiovascular system(increases the risk of developing ventricular arrhythmias). Formoterol and beta-blockers may mutually suppress each other's effects when administered simultaneously. Beta blockers may not only interfere with pharmacological action beta-agonists, but can also cause severe bronchospasm in patients with bronchial asthma.

Overdose

Symptoms: angina attack, arterial hyper- or hypotension, tachycardia (more than 200 beats/min), arrhythmia, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitations, nausea, dizziness, fatigue, weakness, hypokalemia, hyperglycemia, insomnia, metabolic acidosis. Cardiac arrest and death are possible (as with all inhaled sympathomimetics). The minimum lethal dose for rats receiving formoterol fumarate inhalation was 156 mg/kg (approximately 53,000 and 25,000 times the inhalation MDV for adults and children, respectively, based on body surface area in mg/m2).

Treatment: discontinuation of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should be carried out taking into account possible risk development of bronchospasm. Data on the effectiveness of dialysis for formoterol fumarate overdose are insufficient.

Directions for use and doses

Inhalation. Bronchial asthma (maintenance therapy): adults and children 5 years of age and older - 12 mcg every 12 hours. Prevention of attacks of bronchial asthma caused by physical activity: adults and children 5 years and older - 12 mcg 15 minutes before the expected load. Repeated administration is possible no earlier than 12 hours after the previous inhalation. COPD (maintenance therapy): 12 mcg every 12 hours. The maximum recommended dose is 24 mcg/day.

Precautionary measures

Long-acting beta2-adrenergic agonists may increase the risk of death from asthma. In this regard, in the treatment of bronchial asthma, formoterol fumarate should be used only in addition to treatment in patients who do not achieve an adequate effect when prescribing other drugs for the treatment of bronchial asthma (for example, when prescribing low or moderate doses of inhaled glucocorticoids) or in cases where the severity of the disease requires the use of two types of therapy, including formoterol fumarate. Data from a large placebo-controlled study in the United States comparing the safety of another long-acting beta2-adrenergic agonist (salmeterol) and placebo when added to conventional asthma therapy showed that salmeterol resulted in an increased risk fatal outcome compared to placebo. These findings may also apply to formoterol fumarate, which is a long-acting beta2-adrenergic receptor agonist.

Formoterol fumarate is not intended to relieve an attack of bronchial asthma. If while taking formoterol fumarate in the past effective dosage asthma attacks begin to occur or the patient requires more inhalations of beta 2 agonists than usual short acting, urgent consultation with a doctor is necessary, since this common signs destabilization of the state. In this case, therapy should be reviewed and additional treatments prescribed (anti-inflammatory therapy, such as corticosteroids); An increase in the daily dose of formoterol fumarate is unacceptable. The frequency of inhalations should not be increased (more than 2 times a day). Formoterol fumarate should not be used in patients with visible worsening or acute decompensation of asthma, as this may cause life threatening situations.

Like other inhaled beta 2 -agonists, formoterol fumarate can cause paradoxical bronchospasm; in this case, formoterol fumarate should be stopped immediately and alternative treatment. In many patients, monotherapy with beta 2-agonists does not provide adequate control of asthma symptoms; such patients require early administration of anti-inflammatory drugs, such as corticosteroids.

There is no evidence of clinically significant anti-inflammatory activity of formoterol fumarate; therefore, it cannot be considered as an alternative to corticosteroids. Formoterol fumarate is not intended to replace corticosteroids taken by inhalation or by mouth; You should not stop taking or reduce the dose of corticosteroids. Treatment with corticosteroids in patients who have previously taken these drugs orally or inhaled should be continued, even if the patient's well-being has improved as a result of taking formoterol fumarate. Any changes in the dose of corticosteroids, in particular reductions, should be based only on clinical assessment of the patient's condition.

Like other beta 2-adrenergic receptor agonists, formoterol fumarate can cause clinically significant cardiovascular effects (increased heart rate, increased blood pressure, etc.) in some patients; in such cases, formoterol fumarate should be discontinued. Similar to other beta 2 -agonists, formoterol can cause clinically significant hypokalemia (possibly due to intracellular ion redistribution), which contributes to the development of cardiovascular side effects. Decreases in serum potassium levels are usually transient and do not require replacement.

In patients with bronchial asthma, the use of beta-blockers, incl. For secondary prevention myocardial infarction is undesirable. In such cases, the use of cardioselective beta-blockers should be considered, although they should be used with caution.

special instructions

additional literature

Physician Desk Reference.- 63rd ed.- Thomson PDR.- 2009.- P. 2849-2855.

Year of last adjustment

2009

Interactions with other active ingredients

Disopyramide*	Formoterol should be prescribed with caution to patients receiving disopyramide (prolongs the QT interval), as this may potentiate the effect of formoterol on cardiovascular events (increases the risk of developing ventricular arrhythmias).
Procainamide*	Formoterol should be prescribed with caution to patients receiving procainamide (prolongs the QT interval), as this may potentiate the effect of formoterol on cardiovascular events (increases the risk of developing ventricular arrhythmias).
Quinidine	Formoterol should be prescribed with caution to patients receiving quinidine (prolongs the QT interval), as this may potentiate the effect of formoterol on cardiovascular events (increases the risk of developing ventricular arrhythmias).

Catad_pgroup Antiasthmatic drugs

Foradil - official instructions by application

INSTRUCTIONS
by application medicinal product for medical use

Registration number:

Tradename:

International Nonproprietary Name (INN):

formoterol

Dosage form:

capsules with powder for inhalation

Compound:

1 capsule contains:
active substance – formoterol fumarate 0.012 mg;
excipient– lactose up to 25 mg.

Description: transparent, colorless capsules, marked CG on the cap and FXF on the body or CG on the body and FXF on the cap in black ink. Capsule size No. 3.
Capsule contents: white easily free-flowing powder.

Pharmacotherapeutic group:

selective beta2-adrenergic agonist

ATX code: R03AC13.

Pharmacological properties

Pharmacodynamics
Formoterol is a selective beta2-adrenergic receptor agonist. It has a bronchodilator effect in patients with reversible airway obstruction. The effect of the drug occurs quickly (within 1-3 minutes) and lasts for 12 hours after inhalation. Using therapeutic doses the effect on the cardiovascular system is minimal and is observed only in in rare cases.
Foradil inhibits the release of histamine and leukotrienes from mast cells. Animal experiments have shown some anti-inflammatory properties of formoterol, such as the ability to inhibit the development of edema and the accumulation of inflammatory cells.
In vitro animal studies have shown that racemic formoterol and its (R,R) and (S,S) enantiomers are highly selective beta2-adrenergic receptor agonists. The (S,S) enantiomer was 800-1000 times less active than the (R,R) enantiomer and had no effect negative impact on the activity of the (R,R) enantiomer in relation to the effect on tracheal smooth muscle. There has been no pharmacological evidence of benefit from using one of these two enantiomers over the racemic mixture.
In human studies, formoterol has been shown to be effective in preventing bronchospasm caused by inhaled allergens, exercise, cold air, histamine, or methacholine. Since the bronchodilator effect of formoterol remains pronounced for 12 hours after inhalation, prescribing the drug 2 times a day for long-term maintenance therapy allows in most cases to ensure necessary control bronchospasm with chronic diseases lungs, both during the day and at night.
In patients with chronic obstructive pulmonary disease (COPD) stable flow formoterol, used in the form of inhalations from an Aerolyzer in doses of 12 or 24 mcg 2 times a day, causes a rapid onset of a bronchodilator effect that lasts for at least 12 hours and is accompanied by an improvement in quality of life parameters.
Pharmacokinetics
The therapeutic dose range for formoterol is 12 mcg to 24 mcg twice daily. Data on the pharmacokinetics of formoterol were obtained from healthy volunteers after inhalation of formoterol in doses above the recommended range and in patients with COPD after inhalation of formoterol in therapeutic doses.
Suction.
After a single inhalation of formoterol fumarate at a dose of 120 mcg to healthy volunteers, formoterol was rapidly absorbed into the plasma, maximum concentration formoterol plasma (Cmax) was 266 pmol/l and was achieved within 5 minutes after inhalation.
In COPD patients receiving formoterol at a dose of 12 or 24 mcg twice daily for 12 weeks, plasma formoterol concentrations measured at 10 minutes, 2 hours and 6 hours after inhalation were in the ranges of 11.5-25.7 pmol/L and 23.3 -50.3 pmol/l, respectively.
In studies that examined the total urinary excretion of formoterol and its (R,R) and (S,S) enantiomers, it was shown that the amount of formoterol in the systemic circulation increases in proportion to the size of the inhaled dose (12-96 mcg).
After inhaled use of formoterol at a dose of 12 or 24 mcg 2 times a day for 12 weeks, the urinary excretion of unchanged formoterol in patients with bronchial asthma increased by 63-73%, and in patients with COPD - by 19-38%. This indicates some accumulation in the plasma after repeated inhalations. However, there was no greater accumulation of one of the enantiomers of formoterol compared to the other after repeated inhalations.
As has been reported for other inhaled medicinal products, most of the formoterol administered by inhalation will be swallowed and then absorbed from the inhaler. gastrointestinal tract(Gastrointestinal tract). When 80 mcg of 3H-labeled formoterol was administered orally to two healthy volunteers, at least 65% of the formoterol was absorbed.
Plasma protein binding and distribution.
Formoterol binding to plasma proteins is 61-64%, binding to serum albumin is 34%.
In the concentration range observed after the use of therapeutic doses of the drug, saturation of binding sites is not achieved.
Metabolism.
The main route of metabolism of formoterol is direct conjugation with glucuronic acid. Another metabolic pathway is O-demethylation followed by conjugation with glucuronic acid (glucuronidation).
Minor metabolic pathways include conjugation of formoterol with sulfate followed by deformylation. Multiple isoenzymes are involved in glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of formoterol, suggesting a low likelihood drug interactions by inhibiting any isoenzyme involved in the metabolism of formoterol. At therapeutic concentrations, formoterol does not inhibit isoenzymes of the cytochrome P450 system.
Excretion.
In patients with bronchial asthma and COPD who received formoterol fumarate at a dose of 12 or 24 mcg 2 times a day for 12 weeks, approximately 10% and 7% of the dose, respectively, were determined in the urine as unchanged formoterol. The calculated proportions of (R,R) and (S,S) enantiomers of unchanged formoterol in urine are 40% and 60%, respectively, after a single dose of formoterol (12-120 mcg) in healthy volunteers and after single and repeated doses of formoterol in patients with bronchial asthma.
Active substance and its metabolites are completely eliminated from the body; about 2/3 of the dose administered orally is excreted in the urine, 1/3 in feces. The renal clearance of formoterol is 150 ml/min.
In healthy volunteers, the terminal half-life of formoterol from plasma after a single inhalation of formoterol fumarate at a dose of 120 mcg is 10 hours; the terminal half-lives of the (R,R) and (S,S) enantiomers, calculated from urinary excretion, were 13.9 and 12.3 hours, respectively.
Pharmacokinetics separate groups patients
Floor
After correction for body weight, the pharmacokinetic parameters of formoterol in men and women do not differ significantly.
Elderly patients
The pharmacokinetics of formoterol in elderly patients has not been studied.
Pediatrics
In a clinical study in children aged 5-12 years with asthma who received formoterol fumarate at a dose of 12 or 24 mcg 2 times a day for 12 weeks, excretion of unchanged formoterol in urine increased by 18-84% compared with the corresponding indicator. measured after the first dose.
In clinical studies in children, about 6% unchanged formoterol was detected in the urine.
Patients with impaired liver and/or kidney function
The pharmacokinetics of formoterol in patients with impaired liver and/or renal function have not been studied.

Indications for use

Prevention and treatment of bronchial obstruction in patients with bronchial asthma as an addition to therapy with inhaled glucocorticosteroids.
Prevention of bronchospasm caused by exercise, cold air or inhaled allergens as an adjunct to inhaled corticosteroid therapy.
Prevention and treatment of bronchial obstruction in patients with chronic obstructive pulmonary disease (COPD), in the presence of both reversible and irreversible bronchial obstruction, chronic bronchitis and emphysema.

Contraindications

Hypersensitivity to any of the components of the drug
Childhood up to 5 years
Lactation

Carefully

If you have one of the listed diseases, be sure to consult your doctor before using the drug.
Accompanying illnesses
Particular caution when using Foradil (especially in terms of dose reduction) and careful monitoring of patients is required in the presence of the following concomitant diseases: ischemic disease hearts; violations heart rate and conduction, especially third degree atrioventricular block; severe heart failure; idiopathic hypertrophic subaortic stenosis; severe arterial hypertension; aneurysm; pheochromocytoma; hypertrophic obstructive cardiomyopathy; thyrotoxicosis; known or suspected prolongation of the QTc interval (QT corrected > 0.44 sec).
Considering the hyperglycemic effect characteristic of beta2-adrenergic agonists, additional regular monitoring of blood glucose concentrations is recommended in patients with diabetes mellitus taking Foradil.

Use during pregnancy and breastfeeding

The safety of formoterol during pregnancy and breastfeeding has not yet been established.
The use of the drug during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. The drug Foradil, like other beta2-agonists, can slow down the process of labor due to its tocolytic effect (relaxing effect on the smooth muscles of the uterus).
It is not known whether formoterol penetrates into breast milk. Therefore, if it is necessary to use the drug Foradil, breastfeeding must be stopped.
There is no data on the effect of the drug on fertility. Studies in experimental animals have shown no effect on fertility when oral administration formoterol.

Directions for use and doses

The drug Foradil is intended for inhalation use in adults and children aged 5 years and older. The drug is not intended for oral administration. The dose of the drug is selected individually depending on the needs of the patient. Should be used lowest dose, providing therapeutic effect. When control of bronchial asthma symptoms is achieved during therapy with Foradil, it is necessary to consider the possibility of gradually reducing the dose of the drug. Reducing the dose of Foradil is carried out under regular medical supervision of the patient’s condition.
The drug is a powder for inhalation, which should be used only with the help of a special device - an Aerolyzer, which is included in the package.
Adults
At bronchial asthma the dose of the drug for regular maintenance therapy is 12-24 mcg (contents of 1-2 capsules) 2 times a day.
Foradil should only be used as a complementary therapy to inhaled glucocorticosteroids.
The maximum recommended dose of the drug for adults (48 mcg per day) should not be exceeded.
Considering that the maximum daily dose of Foradil is 48 mcg, if necessary, an additional 12-24 mcg per day can be used to relieve the symptoms of bronchial asthma. If the need for additional doses of the drug ceases to be episodic (for example, it becomes more often than 2 days a week), the patient should be advised to consult with a doctor about reviewing therapy, as this may indicate a worsening of bronchial asthma.
Against the background of exacerbation of bronchial asthma, you should not start treatment with Foradil or change the dose of the drug. The drug Foradil should not be used for relief acute attacks bronchial asthma.
To prevent bronchospasm caused by physical activity or unavoidable exposure to a known allergen, 15 minutes before the expected contact with the allergen or before the load, 12 mcg of the drug (contents of 1 capsule) should be inhaled. Patients with a history of severe bronchospasms may require inhalation of the contents of 2 capsules (24 mcg) for prevention.
For COPD the dose of the drug for regular maintenance therapy is 12-24 mcg (contents of 1-2 capsules) 2 times a day.
Children aged 5 years and older
The maximum recommended dose of the drug is 24 mcg per day.
For bronchial asthma The dose of the drug for regular maintenance therapy is 12 mcg 2 times a day. The drug Foradil should be used only as additional therapy to inhaled glucocorticosteroids.
In children aged 5 to 12 years, it is recommended to use combination drugs containing an inhaled glucocorticosteroid and a long-acting beta2-adrenergic receptor agonist, unless it is necessary to use them separately.
With the aim of prevention of bronchospasm caused by physical activity or unavoidable exposure to a known allergen, 15 minutes before expected contact with the allergen or before exercise, the contents of 1 capsule (12 mcg) should be inhaled.
Instructions for inhalation
To ensure proper use of the drug, a doctor or other health care professional must show the patient how to use the inhaler; Explain to the patient that capsules with powder for inhalation should be used only with the help of an Aerolyzer; Warn the patient that the capsules are for inhalation use only and are not intended to be swallowed.
Children should use the drug under adult supervision.
Elderly patients (over 65 years old)
There is no evidence to support the need to use the drug at a different dose in patients over 65 years of age compared to younger patients.
It is important that the patient understands that due to the breakdown of the gelatin capsule, small pieces of gelatin may enter the mouth or throat as a result of inhalation. In order to reduce this phenomenon At a minimum, the capsule should not be pierced more than once.
Remove the capsule from the blister pack immediately before use. (See also Instructions for use of the Aerolyzer).
There are isolated reports of patients accidentally swallowing capsules of the drug whole. Most of these cases are not associated with the development of adverse events. Medical worker must explain to the patient how to use the drug correctly, especially if the patient’s breathing does not improve after inhalation.

Side effect

Adverse reactions (AEs) are distributed according to frequency of occurrence. To estimate the frequency we used following criteria: very often (≥1/10); often (from ≥1/100,<1/10); нечасто (≥1/1000, <1/100); редко (≥1/10000, <1/1000); очень редко (<1/10000), включая отдельные сообщения.
Immune system disorders: very rarely - hypersensitivity reactions, such as decreased blood pressure, urticaria, angioedema, itching, rash.
Mental disorders: infrequently – agitation, anxiety, increased excitability, insomnia.
Nervous system disorders: often – headache, tremor; infrequently - dizziness; very rarely - taste disturbances.
Cardiac disorders: often – a feeling of palpitations; infrequently - tachycardia; very rarely - peripheral edema.
infrequently – bronchospasm, including paradoxical.
General disorders and disorders at the injection site: uncommon – irritation of the mucous membrane of the pharynx and larynx.
Gastrointestinal disorders: uncommon – dryness of the oral mucosa; very rarely - nausea.
Musculoskeletal and connective tissue disorders: uncommon – muscle spasm, myalgia.
According to post-marketing observations, the following AEs were observed when prescribing the drug Foradil, the frequency of which, due to the small number of patients, was regarded as “frequency unknown”:
Laboratory and instrumental data: hypokalemia and hyperglycemia, prolongation of the QT interval on the electrocardiogram, increased blood pressure (including arterial hypertension).
Disorders of the respiratory system, chest and mediastinal organs: cough.
Disorders of the skin and subcutaneous tissues: rash.
Cardiac disorders: angina pectoris, cardiac arrhythmia (including atrial fibrillation, ventricular extrasystoles, tachyarrhythmia).
In clinical studies, formoterol showed a slight increase in the incidence of serious exacerbations of asthma compared to placebo. However, the results of the above clinical studies do not allow us to quantify the incidence of serious exacerbations of bronchial asthma in different groups.
If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Symptoms An overdose of Foradil can likely lead to the development of phenomena characteristic of an overdose of beta2-adrenergic agonists or increased manifestations of side effects: chest pain, nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia up to 200 beats/min, ventricular arrhythmias , metabolic acidosis, hypokalemia, hyperglycemia, increased or decreased blood pressure, nervousness, convulsions, muscle cramps, dry mouth, dizziness, weakness, anxiety. As with all inhaled sympathomimetics, an overdose of Foradil can cause cardiac arrest and death.
Treatment. Maintenance and symptomatic therapy is indicated. In serious cases, hospitalization is necessary.
The use of cardioselective beta-blockers may be considered, but only under close medical supervision and extreme caution, as the use of such agents may cause bronchospasm. Monitoring of cardiac indicators is recommended.

Interaction with other drugs

Foradil, as well as other beta2-agonists, should be prescribed with caution to patients receiving drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines, macrolides, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, as well as other drugs, which are known to prolong the QT interval, since in these cases the effect of agonists on the cardiovascular system may be enhanced. When using drugs that can prolong the QT interval, the risk of ventricular arrhythmias increases.
The simultaneous use of other sympathomimetic drugs may lead to worsening of the side effects of Foradil.
Concomitant use of xanthine derivatives, glucocorticosteroids or diuretics may enhance the potential hypokalemic effect of beta2-agonists.
Patients receiving anesthesia using halogenated hydrocarbons are at increased risk of developing arrhythmias.
Beta blockers may weaken the effect of Foradil. In this regard, Foradil should not be used in conjunction with beta-blockers (including eye drops), unless the use of such a combination of drugs is forced by any emergency reasons.

special instructions

Patients with hypersensitivity to lactose should note that the drug contains lactose.
Foradil belongs to the class of long-acting beta2-adrenergic receptor agonists. Another long-acting beta2-adrenergic agonist (salmeterol) was associated with an increased incidence of asthma-related deaths (13 of 13,176 patients) compared with placebo (3 of 13,179 patients). Clinical studies have not been conducted to assess the incidence of deaths associated with bronchial asthma during the use of Foradil.
It has been shown that the use of Foradil improves the quality of life of patients with COPD.
Anti-inflammatory therapy
In patients with bronchial asthma, Foradil should be used only as an adjunctive treatment in cases of insufficient control of symptoms on monotherapy with inhaled corticosteroids or in severe forms of the disease requiring the use of a combination of an inhaled corticosteroid and a long-acting beta2-adrenergic agonist. The drug should not be used with other long-acting beta2-adrenergic receptor agonists.
When prescribing Foradil, it is necessary to assess the condition of patients regarding the adequacy of the anti-inflammatory therapy they receive. After starting treatment with Foradil, patients should be advised to continue anti-inflammatory therapy without changes, even if improvement is noted.
To relieve an acute attack of bronchial asthma, beta2-adrenergic receptor agonists should be used. If the condition suddenly worsens, patients should seek medical help immediately.
Severe exacerbations of bronchial asthma
In clinical studies, with the use of formoterol, there was a slight increase in the incidence of severe exacerbations of bronchial asthma compared to placebo, especially in children 5-12 years of age.
In placebo-controlled clinical studies in patients receiving formoterol for 4 weeks, there was an increase in the incidence of severe exacerbations of bronchial asthma (0.9% with a dosage regimen of 10-12 mcg 2 times a day, 1.9% with a dosage regimen of 10-12 mcg 2 times a day, 1.9% with a dosage regimen of 24 mcg 2 times a day day) compared to the placebo group (0.3%), especially in children 5-12 years old.
Hypokalemia
Therapy with beta2-agonists, including Foradil, may result in the development of potentially serious hypokalemia. Hypokalemia may increase the risk of developing arrhythmias.
Since this effect of the drug can be enhanced by hypoxia and concomitant treatment, special caution should be observed in patients with severe bronchial asthma. In these cases, regular monitoring of serum potassium concentration is recommended.
Paradoxical bronchospasm
As with other inhalation therapy, the possibility of developing paradoxical bronchospasm should be taken into account. If it occurs, the drug should be discontinued immediately and alternative treatment should be prescribed.

Impact on the ability to drive vehicles and/or operate machinery

Patients who experience dizziness or other disorders of the central nervous system while using the drug Foradil should refrain from driving vehicles or operating machinery while using the drug.

Release form

Capsules with powder for inhalation, 12 mcg, 10 capsules in a blister. 3 or 6 blisters along with instructions for use and an inhalation device Aerolizer in a cardboard box.

Storage conditions

At a temperature not higher than 25°C. Protect from moisture.
Keep out of the reach of children.

Best before date

2 years
The drug should not be used after the expiration date.

Conditions for dispensing from pharmacies

On prescription

Manufacturer

NOVARTIS PHARMA AG, SWITZERLAND/NOVARTIS PHARMA AG, SWITZERLAND
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
NOVARTIS FARMACEUTICA S.A., SPAIN
Address:
Lichtstrasse 35, 4056 Basel, Switzerland
Lichtstrasse 35, 4056 Basel, Switzerland
Additional information about the drug can be obtained at:
125315, Moscow, Leningradsky prospect, building 72, building 3.

Instructions for use of the Aerolyzer

	1. Remove the cap from the Aerolizer.
	2. Hold the Aerolizer firmly by the base and turn the mouthpiece in the direction of the arrow
	3. Place the capsule in the cell located at the base of the Aerolyzer (it is shaped like a capsule). Remember that you need to remove the capsule from the blister pack immediately before inhalation.
	4. Turn the mouthpiece to close the Aerolizer.
	5. Holding the Aerolizer in a strictly vertical position, once Press all the way down on the blue buttons located on the sides of the Aerolizer. Then release them. Note. At this stage, if the capsule is pierced, it may break, causing small pieces of gelatin to get into your mouth or throat. Since gelatin is edible, it will not cause you any harm. To ensure that the capsule does not collapse completely, the following requirements must be met: do not pierce the capsule more than once; follow storage rules; remove the capsule from the blister only immediately before inhalation.
	6. Exhale completely.
	7. Place the mouthpiece in your mouth and tilt your head back slightly. Cover the mouthpiece tightly with your lips and take a quick, even, as deep breath as possible. You should hear a characteristic rattling sound created by the rotation of the capsule and spraying of the powder. If you do not hear a characteristic sound, then you need to open the Aerolizer and see what happened to the capsule. It may be stuck in the cell. In this case, you need to carefully remove the capsule. Under no circumstances should you attempt to release the capsule by repeatedly pressing the buttons on the sides of the Aerolizer.
	8. If you hear a characteristic sound when inhaling, hold your breath as long as possible. At the same time, remove the mouthpiece from your mouth. Then exhale. Open the Aerolyzer and see if there is any powder left in the capsule. If there is powder left in the capsule, repeat the steps described in steps 6-8.
	9. After completing the inhalation procedure, open the Aerolyzer, remove the empty capsule, close the mouthpiece and close the Aerolyzer with the cap. How to care for Arolizer To remove any remaining powder, wipe the mouthpiece and chamber dry cloth. You can also use a soft brush.

Release form: Solid dosage forms. Dosed powder for inhalation.

General characteristics. Compound:

Active ingredient: 12 mcg formoterol fumarate dihydrate.

Excipients: sodium benzoate, lactose monohydrate.

Capsule: hypromellose, caramel color (E 150c).

Pharmacological properties:

Pharmacodynamics.Formoterol is a selective β2-adrenergic receptor agonist (β2-adrenergic agonist). It has a bronchodilator effect in patients with reversible airway obstruction. The effect of the drug occurs quickly (within 1-3 minutes) and lasts for 12 hours after inhalation. When using therapeutic doses, the effect on the cardiovascular system is minimal and is observed only in rare cases.

Formoterol inhibits the release of histamine and leukotrienes from mast cells. Animal experiments have shown some anti-inflammatory properties of formoterol, such as the ability to inhibit the development of edema and the accumulation of inflammatory cells.

In vitro animal studies have shown that racemic formoterol and its (R,R) and (S,S) enantiomers are highly selective β2 receptor agonists. The (S,S) enantiomer was 800-1000 times less active than the (R,R) enantiomer and did not adversely affect the activity of the (R,R) enantiomer in affecting tracheal smooth muscle. There has been no pharmacological evidence of benefit from using one of these two enantiomers over the racemic mixture.

In human studies, formoterol has been shown to be effective in preventing symptoms caused by inhaled allergens, exercise, cold air, histamine or methacholine. Since the bronchodilatory effect of formoterol remains pronounced for 12 hours after inhalation, prescribing the drug 2 times a day for long-term maintenance therapy allows, in most cases, to provide the necessary control of bronchospasm in chronic lung diseases, both during the day and at night.

In patients with chronic obstructive pulmonary disease (COPD) with a stable course, formoterol, used in the form of inhalations in doses of 12 or 24 mcg 2 times a day, is accompanied by an improvement in quality of life parameters.

Pharmacokinetics.The therapeutic dose range for formoterol is 12 mcg to 24 mcg twice daily. Data on the pharmacokinetics of formoterol were obtained in healthy volunteers after inhalation of formoterol in doses above the recommended range and in patients with COPD after inhalation of formoterol in therapeutic doses.

Suction. After a single inhalation of formoterol at a dose of 120 mcg to healthy volunteers, formoterol is rapidly absorbed into the blood plasma, the maximum concentration of formoterol in the blood plasma (Cmax) is 266 pmol/l and is achieved within 5 minutes after inhalation. In patients with COPD who received formoterol at a dose of 12 or 24 mcg 2 times a day for 12 weeks, plasma formoterol concentrations measured at 10 minutes, 2 hours and 6 hours after inhalation were in the range of 11.5-25.7 pmol/l and 23.3-50.3 pmol/l, respectively.

In studies that examined the total urinary excretion of formoterol and its (R,R) and (S,S) enantiomers, it was shown that the amount of formoterol in the systemic circulation increases in proportion to the size of the inhaled dose (12-96 mcg).

After inhaled use of formoterol at a dose of 12 or 24 mcg 2 times a day for 12 weeks, the urinary excretion of unchanged formoterol in patients with bronchial asthma (BA) increased by 63-73%, and in patients with COPD - by 19-38%. This indicates some accumulation of formoterol in the blood plasma after repeated inhalations. However, there was no greater accumulation of one of the enantiomers of formoterol compared to the other after repeated inhalations.

Most formoterol administered by inhaler is swallowed and then absorbed from the gastrointestinal (GI) tract. When 80 mcg of 3H-labeled formoterol was administered orally to two healthy volunteers, at least 65% of the formoterol was absorbed.

Distribution. Formoterol binding to plasma proteins is 61-64%, binding to serum albumin is 34%. In the concentration range observed after the use of therapeutic doses of the drug, saturation of binding sites is not achieved.

Metabolism. The main route of metabolism of formoterol is direct conjugation with glucuronic acid. Another metabolic pathway is O-demethylation followed by conjugation with glucuronic acid (glucuronidation).

Minor metabolic pathways include conjugation of formoterol with sulfate followed by deformylation. Multiple isoenzymes are involved in the processes of glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of formoterol, which suggests a low likelihood of drug interactions through inhibition of any or an isoenzyme involved in the metabolism of formoterol. At therapeutic concentrations, formoterol does not inhibit isoenzymes of the cytochrome P450 system.

Excretion. When taking formoterol in a dose of 12 or 24 mcg 2 times a day for 12 weeks, 10% and 15-18% of the total dose are excreted unchanged in the urine in patients with asthma; 7% and 6-9% of the total dose, respectively, in patients with COPD.

The calculated proportions of (R,R) and (S,S) enantiomers of unchanged formoterol in urine are 40% and 60%, respectively, after a single dose of formoterol (12-120 μg) in healthy volunteers and after single and repeated doses of formoterol in patients with asthma .

The active substance and its metabolites are completely eliminated from the body; about 2/3 of the dose administered orally is excreted in the urine, 1/3 in feces. The renal clearance of formoterol is 150 ml/min.

In healthy volunteers, the terminal half-life of formoterol from plasma after a single inhalation of formoterol at a dose of 120 mcg is 10 hours; the terminal half-lives of the (R,R) and (S,S) enantiomers, calculated from urinary excretion, are 13.9 and 12.3 hours, respectively.

Pharmacokinetics in certain groups of patients. Floor. After adjustment for body weight, the pharmacokinetic parameters of formoterol in men and women do not differ significantly.

Elderly patients (over 65 years old).There is no evidence to support the need to change the dosage of formoterol in patients over 65 years of age compared to younger patients.

Patients with impaired liver and/or kidney function.The pharmacokinetics of formoterol in patients with impaired liver and/or renal function have not been studied.

Indications for use:

Prevention and treatment of bronchial obstruction in patients with bronchial asthma (BA) as an addition to therapy with inhaled glucocorticosteroids.

Prevention of bronchospasm caused by inhaled allergens, cold air or exercise as an adjunct to inhaled glucocorticosteroid therapy.

Prevention and treatment of bronchial obstruction in patients with chronic obstructive pulmonary disease (COPD), in the presence of both reversible and irreversible bronchial obstruction, chronic bronchitis and emphysema.

Important! Get to know the treatment

Directions for use and dosage:

Formoterol-native is intended for inhalation use in patients inover 18 years of age. The drug is not intended for oral administration.

The dose of the drug Formoterol-native is selected individually depending onpatient needs. The lowest dose that providestherapeutic effect. When asthma symptoms are controlled byduring therapy with Formoterol-native, it is necessary to consider the possibilitygradual reduction of the drug dose. Reducing the dose of Formoterol-nativecarried out under regular medical supervision of the patient’s condition.

The drug is a capsule with powder for inhalation, which should beuse only with the help of a special device - the Inhaler CDM® inhaler,which is included in the packaging.

Bronchial asthma.Dose of Formoterol-native for regular maintenance therapyFormoterol native should only be used as adjunctive therapy toinhaled glucocorticosteroids (GCS). The maximum should not be exceededThe recommended dose of the drug is 48 mcg (contents of 4 capsules) per day.Considering that the maximum daily dose of Formoterol-native is 48mcg, if necessary, you can additionally use 12-24 mcg per day forrelief of symptoms of bronchial asthma.

If there is a need to use additional doses of Formoterol-nativeceases to be episodic (for example, becomes more often than 2 days a week), thismay indicate a worsening of bronchial asthma, you should consult a doctor.Against the background of exacerbation of bronchial asthma, treatment with the drug should not be started.Formoterol-native or change the dosage of the drug.Formoterol native should not be used to relieve acute attacksbronchial asthma.

Prevention of bronchospasm caused by exercise or unavoidableexposure to a known allergen.Formoterol-native should be used in a dose of 12 mcg (contents of 1 capsule) for 15minutes before expected contact with the allergen or before exercise. AdditionalInhalation of the drug should not be carried out within the next 12 hours.

Prevention of severe bronchospasms.Patients with a history of severe bronchospasm may require a singleinhalation at a dose of 24 mcg (contents of 2 capsules).

COPD Dose of Formoterol-native for regular maintenance therapy of COPDis 12-24 mcg (contents of 1-2 capsules) 2 times a day.

Instructions for inhalation.To ensure proper use of the drug, your doctor or otherthe medical worker must:
1. warn the patient that the capsules are intended for inhalation onlyuse and are not intended for ingestion;
2. explain to the patient that capsules with powder for inhalation should be usedonly using Inhaler CDM®;
3. show the patient how to use the inhaler.The capsule should be removed from the blister packaging immediately before use.

Instructions for use of the Inhaler CDM® inhaler.Powder inhaler "Inhaler CDM®" - a plastic device with a movable toppart and with a retractable compartment for the capsule, about 6 cm high.The Inhaler CDM® is a single-dose inhaler that allows you to dose and inhaledrug in very small doses. The drug Formoterol-native enters the respiratorythe patient's path along with air flows when performing active inspiration throughmouthpiece of the device.Inhaler CDM® is very easy to use. You must follow the step by stepinstructions given below:
Step 1. Remove the transparent cap from the Inhaler CDM® device asshown in Fig. 1.
Step 2. Hold the device firmly with one hand, index and thumbUse your other hand to open the capsule compartment as shown inFig.2. To do this, press PUSH with your index finger.moving part of the Inhaler CDM®, sliding the compartment intothe opposite side.
Step 3. Hold the device with one hand and insert the drug capsuleinto the compartment slot (Fig. 3).
Step 4. Make sure that the capsule is correctly inserted into the slot (Fig. 4).
Step 5. While holding the Inhaler CDM® in a vertical position, closecompartment by pressing your thumb in the opposite direction until it stops,until a click is heard (Fig. 5).
Step 6. Hold the Inhaler CDM® device strictly vertically (Fig. 6).
Step 7 Bring it into working condition as shown in Fig. 7. ForTo do this, press firmly on the mouthpiece so that the arrowapplied to the body, disappeared beyond the boundaries of the lower partdevices to the top line. Then release the mouthpiece toreturning it to its original position. Thus youpuncture the capsule, allowing access to the drug into themouthpiece clearance.Attention: due to the destruction of the gelatin capsule, smallPieces of gelatin may enter the mouth or mouth as a result of inhalation.throat. In order to reduce this phenomenon to a minimum, do notthe capsule should be pierced more than once.
Step 8 Attention: before inhalation you should exhale(Fig. 8). Do not exhale through the mouthpiece!
Step 9 Gently squeeze the Inhaler CDM® mouthpiece with your teeth, tightlywrap your lips around it and take a deep and strong breath throughmouth (Fig. 9). You will hear a vibrating sound inside the storage compartment.capsule, emitted by the capsule when rotating and scatteringdrug. Attention: the mouthpiece should not be chewed or squeezed too hard.teeth! Do not press on the mouthpiece when inhaling. It mayblock the movement of the capsule. Hold your breathfor approximately 10 seconds or longer as possible.Remove the inhaler from your mouth. Exhale slowly. Thenbreathe normally.Repeat steps 8-9 again to ensure inhalation of dose n reparation.
Step 10 After inhalation, open the capsule compartment (step 2), remove the emptycapsule and then close it as shown in Fig. 5. Attention: p When performing inhalation, try not to cover the openings located onsides of the mouthpiece. This may interfere with the free movement of airinside the inhaler, thereby reducing the dispersion of the capsule contents.

Always close the Inhaler CDM® cap tightly after use, thiswill keep the mouthpiece clean.Clean the outside of the mouthpiece regularly (once a week) with a dry cloth.There have been isolated reports of patients accidentally ingesting capsules.the entire drug, without the use of an inhalation device. Most of thesecases are not associated with the development of adverse events. The health worker mustExplain to the patient how to use the drug correctly, especially if after inhalationThe patient does not experience improvement in breathing.

Features of application:

Use during pregnancy and breastfeeding. The safety of formoterol during pregnancy and breastfeeding has not yet been established.

Use during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. Formoterol, like other β2-agonists, can slow down the process of labor due to its tocolytic effect (relaxing effect on the smooth muscles of the uterus).

It is not known whether formoterol passes into breast milk. Therefore, if it is necessary to use formoterol, breastfeeding should be stopped.

There is no data on the effect of the drug on fertility. Studies in experimental animals have shown no effect on fertility with oral formoterol.

Anti-inflammatory therapy. In patients with bronchial asthma, native Formoterol should be used only as an additional treatment in cases of insufficient control of symptoms during monotherapy with inhaled corticosteroids or in severe forms of the disease requiring the use of a combination of inhaled corticosteroids and a long-acting β2-adrenergic agonist. Formoterol native should not be used with other long-acting β2-adrenergic receptor agonists.

When prescribing the drug Formoterol-native, it is necessary to assess the condition of patients regarding the adequacy of the anti-inflammatory therapy that they receive.

After starting treatment with Formoterol-native, patients should be advised to continue anti-inflammatory therapy without changes, even if improvement is noted.

To relieve an acute attack, β2-adrenergic receptor agonists should be used. If the condition suddenly worsens, patients should seek medical help immediately.

Hypokalemia. A consequence of therapy with β2-agonists, including Formoterol native, may be the development of potentially serious hypokalemia. may increase the risk of developing arrhythmias. Since this effect of the drug Formoterol-native can be enhanced by hypoxia and concomitant treatment, special caution should be observed in patients with severe bronchial asthma. In these cases, regular monitoring of serum potassium concentration is recommended.

Paradoxical bronchospasm. Like other inhaled drugs, Formoterol native can cause paradoxical bronchospasm. In this case, the drug should be discontinued immediately and alternative treatment should be prescribed.

The use of formoterol in a dose exceeding 54 mcg/day (more than 4 inhalations) may lead to positive results in doping tests.

Influence on the ability to drive motor vehicles and other vehicles, and to work with moving mechanisms. There are no data on the effect of the drug Formoterol-native on the ability to drive vehicles and operate machinery. In the event of the development of such adverse reactions as, or muscle spasms, it is necessary to refrain from driving vehicles and operating machinery, as well as from engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Side effects:

Adverse reactions are distributed according to frequency of occurrence. Forfrequency assessments used the following criteria: very often (>1/10), often (from 1/100up to 1/10), uncommon (from 1/1000 to 1/100), rare (from 1/10000 to 1/1000), very rare(<1/10000), (включая отдельные сообщения).

Immune system disorders: very rarely - anaphylactic reactions,urticaria, angioedema (Quincke's edema), itching, rash.

Metabolic and nutritional disorders: very rare -.

Mental disorders: infrequently -, increased excitability, insomnia;very rarely - increased fatigue.

Nervous system disorders: often - tremor; infrequently-dizziness; very rarely - a change in taste sensations.

Cardiac disorders: often - palpitations, chest pain; infrequently -tachycardia; very rarely - peripheral; , heart disorderrhythm (including atrial fibrillation, ventricular extrasystoles, tachyarrhythmia).

Vascular disorders: very rarely - decreased blood pressure(hypotension), increased blood pressure (hypertension).

Disorders of the respiratory system, chest and mediastinal organs:often - increased sputum production; uncommon - bronchospasm, includingparadoxical, ; very rarely - .

Gastrointestinal disorders: uncommon - dry mucous membranesmembranes of the oral cavity; very rarely - .

Musculoskeletal and connective tissue disorders: often - pain inback, leg cramps; infrequently - muscle spasm.

General disorders and disorders at the injection site: often - fever; infrequently -irritation of the mucous membrane of the pharynx and larynx.

Laboratory and instrumental data: uncommon - flattening or inversion of the T wave,ST segment depression, prolongation of the QT interval on the electrocardiogram; very rarely - hypokalemia, .

If any of the side effects indicated in the instructions get worse, or you noticeAny other adverse reactions not listed in the instructions, please report this to your doctor.

Interaction with other drugs:

The drug Formoterol-native, as well as other β2-adrenergic agonists, should be taken withuse caution in patients receiving medications such as:quinidine, disopyramide, procainamide, phenothiazines, macrolides, inhibitorsmonoamine oxidases (MAO), tricyclic antidepressants, antihistaminesdrugs, as well as other drugs known to prolong the intervalQT, since in these cases the effect of adrenergic agonists on the cardiovascular systemmay intensify and increase the risk of ventricular arrhythmias.

Concomitant use of other sympathomimetic drugs may lead toaggravation of adverse reactions of the drug Formoterol-native.

Concomitant use of xanthine derivatives, glucocorticosteroids ordiuretics may enhance the potential hypokalemic effect of the drugFormoterol-native.

In patients receiving anesthesia using halogenatedhydrocarbons, the risk of developing arrhythmias increases.

Drugs related to β2-blockers may weaken the effect of the drugFormoterol is native and leads to serious bronchospasm in patients with bronchialasthma. In this regard, the drug Formoterol-native should not be used together withβ2-blockers (including eye drops), unless usedcombinations of drugs are not forced by any emergency reasons.

Contraindications:

Hypersensitivity and/or intolerance to any of the components of the drug.

Age up to 18 years.

Lactation.

Rare hereditary diseases such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully.If you have one of the listed diseases, be sure to consult your doctor before using the drug.Particular caution when using the drug Formoterol-native (especially in terms of dose reduction) and careful monitoring of patients is required in the presence of the following concomitant diseases: ; disturbances of heart rhythm and conduction, especially third degree atrioventricular block; severe heart failure

Symptoms An overdose of formoterol is likely to lead to the developmentphenomena characteristic of an overdose of β2-adrenergic agonists or increasedmanifestations of side effects: chest pain, palpitations, tachycardiaup to 200 udmin, ventricular, increased or decreased arterialpressure, dry mouth, nausea, headache, dizziness, tremor,nervousness, weakness, anxiety, drowsiness, metabolic acidosis, hypokalemia,hyperglycemia, convulsions. As with all inhaled β2-agonists, whenFormoterol overdose can be fatal.

Treatment. Maintenance and symptomatic therapy is indicated. INSerious cases require hospitalization.The use of cardioselective β2-blockers may be considered, but onlyunder close medical supervision, subject to emergency precautionscaution, as the use of such drugs may cause bronchospasm.Monitoring of cardiac indicators is recommended.

Storage conditions:

In a place protected from light at a temperature not exceeding 25 °C.Keep out of the reach of children. Best before date - 2 years. Do not use after the expiration date stated on the package.

Vacation conditions:

On prescription

Package:

Capsules with powder for inhalation, 12 mcg.10 capsules per blister pack made of multilayer aluminum foil andprinted aluminum foil.3 or 6 blister packs with or without an inhalation deviceit, instructions for use are placed in a cardboard box.

Formula: C19H24N2O4, chemical name: (R*,R*)-(±)-N-amino]ethyl]phenyl]formamide (as fumarate).
Pharmacological group: vegetotropic agents / adrenomimetic agents / beta-adrenergic agonists.
Pharmachologic effect: bronchodilator, adrenomimetic.

Pharmacological properties

Formoterol is a selective, long-acting beta2-adrenergic receptor agonist. Formoterol, when inhaled, acts locally on the bronchi, causing them to expand. The activity of formoterol in relation to beta2-adrenergic receptors, which are located mainly in the smooth muscles of the bronchi, is more than 200 times higher than that in relation to beta1-adrenergic receptors, which are located mainly in the myocardium. The myocardium also contains beta2-adrenergic receptors, which account for up to 10–50% of the total number of beta-adrenergic receptors. The exact function of these receptors has not been established, but they increase the risk of developing cardiac reactions even with the use of highly selective beta2-agonists. The main adverse reactions of inhaled beta2-adrenergic agonists develop as a result of excessive activation of systemic beta-adrenergic receptors. Formoterol stimulates adenylate cyclase inside cells, which catalyzes the conversion of adenosine triphosphate to cyclic adenosine monophosphate. An increase in the concentration of cyclic adenosine monophosphate causes relaxation of the smooth muscles of the bronchi and inhibits the liberation of mediators of immediate hypersensitivity from cells (especially from mast cells). It has been established that in human lungs, formoterol inhibits the release of mediators (leukotrienes, histamine) from mast cells. In animal studies, formoterol has been shown to slow allergen-induced eosinophil influx in dogs with airway hyperresponsiveness and histamine-induced extravasation of serum albumin in anesthetized guinea pigs. The significance of these facts for humans is unknown.
Pharmacodynamic and pharmacokinetic relationships between electrocardiographic parameters, heart rate, renal excretion of formoterol and serum potassium concentration were studied in 10 healthy men aged 25 to 45 years with a single inhalation of 12, 24, 48, 96 mcg of the drug. A linear relationship was established between increased plasma glucose concentrations and increased heart rate, decreased serum potassium concentrations, and renal excretion of formoterol. In another study, 12 volunteers received a single dose of 120 mcg of the drug (10 above the recommended single dose). In all subjects, the concentration of potassium in the blood serum decreased as much as possible by 0.55 - 1.52 mmol/l. A strong correlation was noted between formoterol and potassium levels in the blood serum: the greatest effect on potassium concentration was observed 1 to 3 hours after reaching the maximum concentration of the drug. The maximum increase in heart rate, on average, was observed 6 hours after taking the drug and amounted to 26 beats per minute. The maximum prolongation of the corrected QT interval when calculated using Fredericia's formula averaged 8 milliseconds, and according to Bazett's formula - 25 milliseconds. The value of the corrected QT interval returned to the original value 0.5 - 1 day after taking the drug. Serum formoterol levels were weakly correlated with increases in corrected QT interval and heart rate. The effect on pulse rate, plasma potassium concentration, and corrected QT interval are known pharmacological effects of the class of drugs to which formoterol belongs, so their development in studies of very high doses of the drug (120 mcg single dose, 10 times the recommended single dose) was expected. These reactions were well tolerated by healthy volunteers. Formoterol can cause flattening of the T wave, depression of the ST segment on the electrocardiogram; the clinical significance of these changes is unknown.
Studies have shown that tolerance to the bronchoprotective effect of formoterol was observed after 2 weeks of taking the drug, loss of protective properties was noted by the end of the 12-hour period after administration. After cessation of long-term treatment with formoterol, no rebound bronchial hyperreactivity reactions were observed.
With a single inhalation of 120 mcg of the drug in 12 healthy volunteers, formoterol was rapidly absorbed into the plasma, reaching a maximum concentration (92 pg/ml) within 5 minutes. In patients with chronic obstructive pulmonary disease who received the drug at a dose of 12 or 24 mcg twice daily for 12 weeks, the average plasma concentration of formoterol was 4.0 - 8.8 pg/ml and 8.0 - 17.3, respectively. pg/ml. When 12–96 mcg of the drug was inhaled by 10 healthy volunteers, the urinary excretion of S,S- and R,R-enantiomers of formoterol increased in proportion to the dose, thus, in the considered dose range, the absorption of formoterol during inhalation is linear. With repeated use of the drug, there is some accumulation of formoterol in the blood plasma; the accumulation index, which was assessed by the excretion of unchanged drug in the urine, was 1.19 - 2.08. The amount of formoterol eliminated at steady state was almost equal to that predicted based on pharmacokinetics after a single dose. It is believed that most of formoterol (like other inhaled drugs) will be swallowed and then absorbed from the gastrointestinal tract. Formoterol at a concentration of 0.1 - 100 ng/ml in vitro binds to plasma proteins by 61 - 64%, at a plasma concentration of 5 - 500 ng/ml with albumin - 31 - 38% (these concentrations in blood serum are higher than those for inhalation 120 mg of the drug). Formoterol is metabolized mainly by O-demethylation with further binding to a glucuronide at any phenolic hydroxyl group and by direct glucuronidation at an aliphatic or phenolic hydroxyl group. Another way of biotransformation of formoterol is sulfation and deformylation, which is accompanied by sulfation. The main route of metabolism is direct conjugation at the phenolic hydroxyl group, the second most important route is O-demethylation, which is accompanied by conjugation at the phenolic 2"-hydroxyl group. Cytochrome P450 isoenzymes (CYP2C19, CYP2D6, CYP2A6, CYP2C9) are involved in the O-demethylation of formoterol. Formoterol at therapeutic concentrations does not inhibit cytochrome P450 enzymes. When 80 mcg of the radiolabeled drug was administered orally to two healthy volunteers, 32–34% was excreted in feces and 59–62% in urine over 104 hours; renal clearance was approximately 150 ml/ min In 18 patients with chronic obstructive pulmonary disease who received the drug in doses of 12 mcg or 24 mcg, about 7% of the drug was excreted in the urine unchanged and 6–9% in the form of metabolites. In 16 patients with bronchial asthma who received 12 mcg or 24 mcg of the drug by inhalation, approximately 10% of formoterol was excreted in the urine unchanged and 15–18% in the form of metabolites. Following a single inhalation of 120 mcg of the drug in 12 healthy volunteers, the terminal half-life (based on measurements of serum concentrations) was 10 hours. The terminal half-life for the S,S- and R,R-enantiomers of formoterol was 12.3 and 13.9 hours, respectively, when calculated by renal excretion. The proportion of S,S- and R,R-enantiomers of the unchanged substance that was found in the urine was 60% and 40%, respectively.
There were no significant differences in the pharmacokinetic parameters of formoterol depending on gender.
There were no significant differences in the effectiveness and safety of formoterol in elderly and younger patients. The pharmacokinetics of formoterol in elderly patients has not been studied.
In children 5–12 years of age with bronchial asthma who received inhaled doses of the drug at a dose of 12 mcg or 24 mcg twice daily for 12 weeks, the accumulation index, which was calculated from the renal excretion of unchanged formoterol, ranged from 1.18 to 1. 84 (in adults - 1.63 - 2.08). In the urine of children, approximately 6% of formoterol was determined in unchanged form and 6.5–9% in the form of conjugates.
The pharmacokinetics of formoterol in patients with liver or kidney damage have not been studied.
In animal studies (rodents, mini-pigs, dogs), cases of arrhythmias and sudden death with histologically confirmed myocardial necrosis were identified when beta-agonists and methylxanthine derivatives were used together. For humans, the clinical significance of these facts has not been determined.
Formoterol did not exhibit clastogenic or mutagenic properties in the following tests: chromosomal analysis on mammalian cells, mutagenicity studies on mammalian and bacterial cells, micronucleus tests on rats and mice, transformation analysis of mammalian fibroblasts, DNA repair studies on human fibroblasts and rat hepatocytes.
A study of the carcinogenicity of the drug was carried out on mice and rats that received formoterol for 2 years through drinking water or food. At doses of the drug 20 mg/kg or more with food and 15 mg/kg or more with drinking water in rats, the incidence of ovarian leiomyoma increased. When receiving 5 mg/kg of the drug with food (approximately 450 times the area under the concentration-time curve in humans when taking the maximum recommended dose for humans by inhalation), the incidence of ovarian leiomyoma did not increase in rats. When taking the drug with food at a dose equal to or higher than 0.5 mg/kg (the area under the concentration-time curve of a dose of 0.5 mg/kg is approximately 45 times the exposure of the inhalation maximum recommended dose for humans), cases of benign development have increased. theca cell tumors of the ovaries. These facts were not observed in tests on mice or when the drug was administered to rats through drinking water. When receiving 69 mg/kg or more of the drug in drinking water, cases of the development of carcinomas and subcapsular adenomas of the adrenal glands in male mice increased; These tumors did not develop when the drug was taken with food at doses of approximately 50 mg/kg (the area under the concentration-time curve is approximately 590 times higher than human exposure at inhaled doses of the maximum recommended daily dose). When taken with food at 50 mg/kg (in males) and 20 and 50 mg/kg (in females) of the drug, the development of hepatocarcinomas was observed in mice. When taking the drug with food in doses of 2 mg/kg or more (the area under the concentration-time curve at a dose of 2 mg/kg is approximately 25 times higher than the exposure in humans with inhalation administration of the maximum recommended daily dose), the development of leiomyosarcomas and uterine leiomyomas was observed. The increase in the incidence of leiomyomas of the reproductive system in female rodents was similar to data from studies of other beta-agonists.
No fertility impairment was observed in a reproductive study in rats that received the drug orally at doses of approximately 3 mg/kg (approximately 1000 times the maximum recommended daily inhalation dose for humans based on body surface area in mg/m2). In rats that received the drug at a dose of 6 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose for humans, calculated on a body surface area basis in mg/m2) during late pregnancy, neonatal and prenatal mortality increased. When taking the drug at a dose of 0.2 mg/kg (70 times the maximum recommended daily inhalation dose for humans when calculated per body surface area in mg/m2), these effects were not observed. A decrease in weight and a slowdown in ossification of the body skeleton was noted in fetuses of rats that received the drug in doses of 6 mg/kg and 0.2 mg/kg, respectively, during the period of organogenesis. Formoterol did not cause malformations in studies in rabbits and rats.

Indications

Long-term maintenance therapy for bronchial asthma and prevention (in patients over 5 years of age) of bronchospasm in reversible obstructive airway diseases, including patients with symptoms of nocturnal asthma.
Use as needed (“on demand”) is indicated for patients over 5 years of age to quickly prevent bronchospasm caused by physical activity.
Long-term maintenance therapy in patients with chronic obstructive pulmonary disease, including emphysema and chronic bronchitis.

Method of administration of formoterol and dose

Formoterol is used by inhalation. Bronchial asthma (maintenance treatment): 12 mcg every 12 hours. Prevention of bronchial asthma attacks caused by physical activity: 12 mcg 15 minutes before the expected exercise. Repeated administration is possible no earlier than 12 hours after the previous inhalation. Chronic obstructive pulmonary disease (maintenance treatment): 12 mcg every 12 hours. The maximum recommended dose is 24 mcg per day.
Capsules containing formoterol fumarate should not be taken orally; they must be used only by inhalation through a special device. Do not exhale into the inhalation device.
Formoterol is not recommended in patients for whom treatment with inhaled corticosteroids or other medications, one of which is an intermittently inhaled short-acting beta2-agonist, is completely adequate; as well as patients who manage to control bronchial asthma only with non-systematic inhalations of short-acting beta2-adrenergic receptor agonists.
Formoterol is not intended to relieve an attack of bronchial asthma. If, when using formoterol in a previously effective dosage, attacks of bronchial asthma begin to develop or the patient needs a larger than usual number of inhalations of short-acting beta2-agonists, then urgent consultation with a doctor is necessary, as this is a frequent sign of destabilization of the condition. In this case, treatment should be reconsidered and additional therapies should be prescribed (anti-inflammatory treatment, for example, corticosteroids); In this case, increasing the daily dose of formoterol is unacceptable. You cannot increase the frequency of inhalations more than twice a day. Do not use formoterol in patients with acute decompensation or with visible worsening of bronchial asthma, as these situations may be life-threatening.
Long-acting beta2-adrenergic agonists may increase the risk of death from asthma. Therefore, in the treatment of bronchial asthma, formoterol should be used only in addition to therapy in patients who do not achieve an adequate effect when prescribed other drugs for the treatment of bronchial asthma (for example, low or medium doses of inhaled glucocorticoids), or when the severity of the disease requires use two types of treatment, including formoterol. Results from a large placebo-controlled study in the United States comparing the safety of salmeterol (another long-acting beta2-adrenergic agonist) and placebo when added to usual asthma treatment showed that salmeterol increased the risk of death when compared with placebo. These findings may extend to formoterol, which is a long-acting beta2-adrenergic agonist.
Formoterol, like other inhaled beta2-agonists, can cause paradoxical bronchospasm; in this case, it is necessary to stop taking formoterol and prescribe alternative therapy. In many patients, the use of beta2-agonists alone does not provide adequate control of asthma symptoms; such patients require early administration of anti-inflammatory drugs, such as corticosteroids.
Formoterol, like other beta2-adrenergic receptor agonists, can cause clinically significant cardiovascular reactions (increased blood pressure, increased heart rate, etc.) in some patients; in this case, you should stop taking formoterol. Formoterol, like other beta2-adrenergic agonists, can cause clinically significant hypokalemia (probably due to the redistribution of ions within cells), this hypokalemia contributes to the development of adverse reactions from the cardiovascular system. The decrease in plasma potassium concentration is usually transient and does not require replacement.
Formoterol cannot be considered as an alternative to corticosteroids, since there is no evidence of clinically significant anti-inflammatory activity. Formoterol is not intended to replace corticosteroids taken orally or inhaled; Do not reduce the dose or stop taking corticosteroids. Corticosteroid therapy in patients who have previously taken these drugs by inhalation or oral administration should be continued, even if the patient's condition has improved with formoterol. Any changes in the dose of corticosteroids should be based only on clinical assessment of the patient's condition.
In patients with bronchial asthma, the use of beta-blockers, including for secondary prevention of myocardial infarction, is undesirable. In such situations, the use of cardioselective beta-blockers should be considered, but they should be used with caution.
Use formoterol with caution in people whose activities are associated with increased concentration and speed of psychomotor reactions (including driving).

Contraindications for use

Hypersensitivity, age up to 5 years (safety and effectiveness have not been established).

Restrictions on use

Unusual response to sympathomimetics, cardiovascular disorders including arrhythmias, coronary artery disease, cardiac arrhythmia and conduction disturbances (especially third degree atrioventricular block), coronary insufficiency, hypertension, hypertrophic obstructive cardiomyopathy, known or suspected QT prolongation, idiopathic subvalvular aortic stenosis , heart failure; thyrotoxicosis, convulsive disorders, diabetes mellitus, uterine fibroids, breastfeeding, pregnancy.

Use during pregnancy and breastfeeding

Formoterol should be used during pregnancy and childbirth (beta-agonists may have a negative effect on uterine contractility) only when the expected benefit to the mother outweighs the possible risk to the fetus. Strictly controlled and adequate studies of the drug in pregnant women, including during childbirth, have not been conducted. Formoterol should be prescribed with caution to nursing women. There have been no strictly controlled and adequate studies in lactating women. It is not known whether formoterol is excreted into breast milk in women, but many drugs are excreted in human milk. Formoterol is excreted in rat milk.

Side effects of formoterol

Nervous system: tremor, dizziness, insomnia, convulsions, nervousness, headache, calf muscle cramps, anxiety.
Circulatory system: angina pectoris, tachycardia, arterial hypo- or hypertension, arrhythmia, palpitations.
Digestive system: dry mouth, nausea, abdominal pain, dyspepsia, gastroenteritis.
Respiratory system: upper respiratory tract infections, chest infections, bronchitis, dyspnea, pharyngitis, increased amount of sputum, sinusitis, rhinitis, dysphonia, tonsillitis, severe exacerbations of bronchial asthma, including deaths (the connection with formoterol has not been proven).
Others: viral infections, chest pain, myalgia, back pain, rash, itching, fever, trauma, fatigue, weakness, hypokalemia, hyperglycemia, metabolic acidosis, anaphylactic reaction, including angioedema and severe hypotension; allergic reactions, including urticaria and bronchospasm.

Interaction of formoterol with other substances

Other adrenergic drugs should be used with caution when using formoterol, as there is a risk of enhancing the predictable sympathomimetic reactions of formoterol.
The hypokalemic effect of formoterol may be enhanced by the combined use of steroids, xanthine derivatives, and diuretics.
Hypokalemia or changes in the electrocardiogram that are caused by non-potassium-sparing diuretics (thiazide or loop diuretics) may be suddenly worsened by formoterol, especially when the dose of the latter is increased; Caution is necessary when using these drugs together.
Formoterol should be prescribed with special attention when taking tricyclic antidepressants, monoamine oxidase inhibitors or other drugs that can prolong the QT interval, as this may enhance the effect of formoterol on the circulatory system (increases the risk of developing ventricular arrhythmias).
Beta-blockers (including in the form of eye drops) and formoterol, when used together, can mutually suppress each other's effects; in addition, beta-blockers can cause severe bronchospasm in patients with bronchial asthma.
When used together, disopyramide, quinidine, procainamide, tricyclic antidepressants, antihistamines, and phenothiazines increase the risk of developing ventricular arrhythmias.

Overdose

In case of an overdose of formoterol, an attack of angina pectoris, tachycardia (more than 200 beats per minute), arterial hypo- or hypertension, palpitations, arrhythmia, dry mouth, nausea, headache, nervousness, dizziness, weakness, fatigue, insomnia, tremor, muscle cramps, develop. seizures, metabolic acidosis, hyperglycemia, hypokalemia; cardiac arrest and death are possible. The minimum lethal dose for rats that received the drug by inhalation was 156 mg/kg (approximately 25,000 and 53,000 times the maximum recommended inhalation dose for children and adults, respectively, based on body surface area in mg/m2).
Treatment: withdrawal of formoterol, supportive and symptomatic treatment, electrocardiography monitoring. The use of cardioselective beta-blockers should be carried out taking into account the risk of bronchospasm. Data on the effectiveness of dialysis are insufficient.

Trade names of drugs with the active substance formoterol

Combined drugs:
Budesonide + Formoterol: Symbicort® Turbuhaler®;
Beclomethasone + Formoterol: Foster;
Budesonide + Formoterol [set]: Foradil Combi;
Mometasone + Formoterol: Zenhale.