"Formoterol" - a tool that allows you to breathe deeply. Formoterol (Formoterol) price comparison for synonyms, availability in pharmacies Restrictions on use and contraindications
Active substance(INN) Formoterol (Formoterol)
Synonyms:
Zafiron, Atimos; Oksis; Oxys Turbuhaler; Foradil; Foradil Aerolizer; Formoterol; Formoterol Easyhaler; Formoterol fumarate.
Rice. Formroterol ( Foradil)
Pharmacokinetics:
Absorption:
Formoterol, when administered orally in a single dose of up to 300 mcg, is rapidly absorbed from the gastrointestinal tract. As has been reported for other inhaled drugs, approximately 90% of inhaled formoterol is expected to be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of oral dosage forms are largely applicable to inhaled dosage forms. When taken orally at a dose of 80 mcg, absorption is about 65%.
The maximum concentration of unchanged active substance is reached within 15 minutes - 1 hour after ingestion.
In the studied dose range (20-300 mcg), administered orally, the pharmacokinetics of formoterol is linear. Repeated oral administration in doses of 40-160 mcg per day did not lead to significant cumulation of the drug.
Distribution and metabolism:
Plasma protein binding is approximately 50% - 65% (primarily binding to albumin - 34%).
In the range of concentrations noted after the use of therapeutic doses of the drug, saturation of the binding sites is not achieved.
The drug is metabolized by direct glucuronidation (addition of a glucuronic acid residue) and o-demethylation, followed by glucuronidation.
Excretion from the body:
Elimination of formoterol from the circulation appears to be polyphasic. The plasma half-life is 8 hours. The active substance and its metabolites are completely eliminated from the body; about 2/3 of the oral dose is excreted in the urine (6-10% unchanged), and 1/3 in the feces. The maximum rate of excretion is reached within 1-2 hours. The half-life of formoterol, calculated from urinary excretion rates observed between 3 and 16 hours after inhalation of the drug, was about 5 hours. Renal clearance of formoterol is 150 ml/min.
Application Formoterol (Formoterol): According to the Physician Desk Reference (2003), formoterol fumarate is indicated for long-term (twice daily - morning and evening) maintenance therapy in bronchial asthma and prevention (in adults and children 5 years and older) of bronchospasm in reversible obstructive diseases respiratory tract, incl. in patients with symptoms of nocturnal asthma who require regular inhalation of short-acting beta2-agonists.
May be used in asthma in conjunction with short-acting beta2-agonists, corticosteroids (systemic or inhaled) and theophylline.
The use of Formoterol (Formoterol) formoterol fumarate "on demand" (if necessary) is indicated for adults and children 12 years of age and older for the rapid prevention of exercise-induced bronchospasm.
Formoterol fumarate is used in patients with COPD, including chronic bronchitis and pulmonary emphysema, for long-term maintenance therapy.
Contraindications Formoterol (Formoterol): Hypersensitivity.
Application restrictions: Cardiovascular disorders, incl. coronary insufficiency, arrhythmias, arterial hypertension, convulsive disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breastfeeding, age up to 5 years (safety and efficacy have not been established).
Formoterol fumarate is not recommended in patients whose asthma is controlled only by non-systematic inhalation of short-acting beta2-adrenergic agonists.
Application of Formoterol (Formoterol) during pregnancy and lactation: 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 (since beta-agonists can adversely affect uterine contractility) only in cases where the intended benefit to the mother outweighs the potential risk to the fetus. Formoterol fumarate is excreted in the milk of rats. It is not known whether it is excreted in breast milk in women, but because many drugs are excreted in human milk, formoterol fumarate should be administered with caution to lactating women (well-controlled studies in lactating women have not been conducted).
Side effects: Side effects of formoterol fumarate are similar to those of other selective beta2-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
In controlled clinical trials, formoterol fumarate (12 mcg 2 times a day) was received by 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 of 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 nervous system and sensory organs: tremor 1.9% (0.4%), dizziness 1.6% (1.5%), insomnia 1.5% (0.8%).
From the respiratory system: bronchitis 4.6% (4.3%), chest infections 2.7% (0.4%), dyspnea 2.1% (1.7%), tonsillitis 1.2% ( 0.7%), dysphonia 1.0% (0.9%).
Other: 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 found to be dose-dependent (doses of 6, 12 and 24 mcg taken twice a day 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 bronchial asthma who needed daily bronchodilators and anti-inflammatory drugs. Against the background of 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. Adverse events in the formoterol fumarate group in children that were higher than those in the placebo group included infections/inflammation (viral infections, rhinitis, tonsillitis, gastroenteritis) or gastrointestinal complaints (abdominal pain, nausea, dyspepsia).
COPD
In two controlled studies, formoterol fumarate (12 mcg twice daily) was administered to 405 patients with COPD. The incidence of adverse events was comparable between the formoterol fumarate and placebo groups. Among the side effects in the formoterol fumarate group with a frequency equal to or greater than 1% and superior to that in the placebo group, the following were noted (next to the name is the percentage of occurrence in the formoterol fumarate group, in brackets - in the placebo group):
From the nervous system and sensory organs: convulsions 1.7% (0%), calf muscle cramps 1.7% (0.5%), anxiety 1.5% (1.2%).
From the respiratory system: infections of the upper respiratory tract 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%), pruritus 1.5% (1, 0%), dry mouth 1.2% (1.0%), injuries 1.2% (0%).
In general, the incidence of all cases of cardiovascular side effects in the two main studies was low and comparable with placebo (6.4% in patients taking 12 mcg of formoterol fumarate twice a day, and 6.0% in the placebo group). Specific cardiovascular side effects in the formoterol fumarate group, occurring at a frequency of 1% or more and exceeding the frequency of occurrence in the placebo group, were noted.
In two studies in patients taking 12 mcg and 24 mcg of formoterol fumarate twice daily, a dose-dependent pattern of seven side effects (pharyngitis, fever, convulsions, increased sputum count, dysphonia, myalgia and tremor) was noted.
Post-marketing research
In the course of the widespread post-marketing use of formoterol fumarate, there have been reports of severe exacerbations of bronchial asthma, some of which ended fatally. Although most of these cases were noted in patients with severe bronchial asthma or acute decompensation of the condition, a few cases were noted in patients with less severe bronchial asthma. The relationship of these cases with the intake of formoterol fumarate has not been determined. There are rare reports of anaphylactic reactions, including severe hypotension and angioedema, associated with inhaled formoterol fumarate. Allergic reactions can manifest as urticaria and bronchospasm. Evidence of the development of drug dependence with the use of formoterol fumarate in clinical trials has not been received.
Interaction: Other adrenergic drugs while taking formoterol should be used with caution, since there is a risk of potentiation of the predicted sympathomimetic effects of formoterol. With the simultaneous administration of xanthine derivatives, steroids or diuretics, the hypokalemic effect of adrenergic agonists may be enhanced. ECG changes and / or hypokalemia due to non-potassium-sparing diuretics, such as loop or thiazide diuretics, can be suddenly aggravated by beta-agonists, especially when the dose of the latter is exceeded (although the clinical significance of these effects is unclear, caution is required when prescribing drugs of these groups simultaneously ). Formoterol, like other beta2-agonists, should be given with special attention while taking MAO inhibitors, tricyclic antidepressants or other drugs that can prolong the QTc interval, since this can potentiate the effect of adrenomimetics on the cardiovascular system (increased risk of developing ventricular arrhythmias) . Formoterol and beta-blockers can mutually suppress each other's effects when administered simultaneously. Beta-blockers can not only interfere with the pharmacological action of 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 bpm), arrhythmia, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitations, nausea, dizziness, fatigue, weakness , hypokalemia, hyperglycemia, insomnia, metabolic acidosis. Possible cardiac arrest and death (as with all inhaled sympathomimetics). The minimum lethal dose for rats treated with inhaled formoterol fumarate was 156 mg/kg (approximately 53,000 and 25,000 times the inhaled MRDH for adults and children, respectively, on a body surface area basis in mg/m2).
Treatment: withdrawal of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should be carried out taking into account the possible risk of developing bronchospasm. Data on the effectiveness of dialysis in overdose of formoterol fumarate are insufficient.
Dosage and administration: Inhalation. Bronchial asthma (maintenance therapy): adults and children 5 years of age and older - 12 mcg every 12 hours. If symptoms of bronchial asthma occur between inhalations, short-acting beta2-agonists should be used. Prevention of asthma attacks caused by physical activity: adults and adolescents 12 years of age and older - 12 mcg 15 minutes before the intended load. Re-introduction is possible no earlier than 12 hours after the previous inhalation. COPD (maintenance therapy): 12 micrograms every 12 hours. The maximum recommended dose is 24 micrograms / day.
Precautionary measures: Formoterol fumarate is not intended for the relief of an attack of bronchial asthma. If, while taking formoterol fumarate at a previously effective dosage, attacks of bronchial asthma began to occur or the patient needs more inhalations of short-acting beta2-agonists than usual, an urgent consultation with a doctor is necessary, since these are frequent signs of destabilization of the condition. 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. Do not increase the frequency of inhalations (more than 2 times a day). Formoterol fumarate should not be used in patients with apparent worsening or acute decompensation of asthma, as these may be life-threatening situations.
When prescribing formoterol fumarate to patients who have previously taken short-acting beta2-agonists as basic therapy (for example, 4 times a day), patients should be warned to stop taking these drugs regularly and use them only as symptomatic therapy for exacerbation of asthma symptoms. Like other inhaled beta2-agonists, formoterol fumarate can cause paradoxical bronchospasm; in this case, formoterol fumarate should be stopped immediately and an alternative treatment instituted. In many patients, monotherapy with beta2-agonists does not provide adequate control of asthma symptoms; such patients require early administration of anti-inflammatory drugs, such as corticosteroids.
There are no data on 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 inhaled or oral corticosteroids; stop taking or reduce the dose of corticosteroids should not be. Treatment with corticosteroids in patients previously taking these drugs by mouth or inhalation should be continued, even if the patient's condition improved as a result of taking formoterol fumarate. Any changes in the dose of corticosteroids, in particular reduction, should be based only on clinical assessment of the patient's condition.
Like other beta2-adrenergic agonists, formoterol fumarate in some patients can cause clinically significant cardiovascular effects (increased heart rate, increased blood pressure, etc.); in such cases, formoterol fumarate should be discontinued. Similar to other beta2-agonists, formoterol can cause clinically significant hypokalemia (possibly due to intracellular redistribution of ions), which contributes to the development of adverse cardiovascular effects. Decreases in serum potassium are usually transient and do not require replacement.
In patients with bronchial asthma, the use of beta-blockers, incl. for secondary prevention of myocardial infarction, is undesirable. In such cases, the appointment of cardioselective beta-blockers should be considered, although they should be used with caution.
Special instructions: Capsules containing formoterol fumarate should not be taken orally; they should only be used by inhalation through a special device. Do not exhale into the inhalation device.
This page contains a list of all Formoterol analogues by composition and indications for use. A list of cheap analogues, and you can also compare prices in pharmacies.
- The cheapest analogue of Formoterol:
- The most popular analogue of Formoterol:
- ATH classification: Formoterol
- Active ingredients / composition: formoterol
Cheap analogues of Formoterol
| # | Name | Price in Russia | Price in Ukraine |
|---|---|---|---|
| 1 | salbutamol | 75 rub | 31 UAH |
| 2 | salbutamol Analogue by indication and method of application | 107 rub | -- |
| 3 | Analogue by indication and method of application | 118 rub | 8 UAH |
| 4 | salbutamol hemisuccinate Analogue by indication and method of application | 119 rub | -- |
| 5 | salbutamol Analogue by indication and method of application | 122 rub | -- |
When calculating the cost cheap analogues of Formoterol the minimum price was taken into account, which was found in the price lists provided by pharmacies
Popular analogues of Formoterol
| # | Name | Price in Russia | Price in Ukraine |
|---|---|---|---|
| 1 | formoterol Analogue in composition and indication | 305 rub | -- |
| 2 | indacaterol Analogue by indication and method of application | -- | 257 UAH |
| 3 | Analogue by indication and method of application | 150 rub | 107 UAH |
| 4 | salbutamol Analogue by indication and method of application | 75 rub | 31 UAH |
| 5 | salbutamol Analogue by indication and method of application | 107 rub | -- |
The list of drug analogues based on the statistics of the most requested drugs
All analogues of Formoterol
The above list of analogues of drugs, which indicates Substitutes Formoterol, is the most suitable, since they have the same composition of active ingredients and match the indications for use
Analogues by indication and method of application
| Name | Price in Russia | Price in Ukraine |
|---|---|---|
| salbutamol | -- | 148 UAH |
| salbutamol | -- | 34 UAH |
| salbutamol | 236 rub | 8 UAH |
| salbutamol | -- | -- |
| salbutamol | 75 rub | 31 UAH |
| 118 rub | 8 UAH | |
| salbutamol | -- | 4 UAH |
| salbutamol | -- | 221 UAH |
| salbutamol | -- | 41 UAH |
| salbutamol | 107 rub | -- |
| salbutamol | -- | -- |
| salbutamol | 122 rub | -- |
| salbutamol sulfate | -- | 46 UAH |
| salbutamol hemisuccinate | 119 rub | -- |
| fenoterol | -- | -- |
| 150 rub | 107 UAH | |
| fenoterol | 304 rub | 107 UAH |
| fenoterol | 125 rub | -- |
| fenoterol | 202 rub | -- |
| salmeterol | 8800 rub | 436 UAH |
| salmeterol | -- | 436 UAH |
| salmeterol | -- | -- |
| indacaterol | -- | 257 UAH |
Different composition, may coincide in indication and method of application
| Name | Price in Russia | Price in Ukraine |
|---|---|---|
| -- | -- | |
| ipratropium bromide, fenoterol | 202 rub | 133 UAH |
| ipratropium bromide, fenoterol | 334 rub | 145 UAH |
| 176 rub | -- | |
| salmeterol, fluticasone propionate | 446 rub | 170 UAH |
| salmeterol, fluticasone | -- | 170 UAH |
| salmeterol xinafoate, fluticasone propionate | 446 rub | 1500 UAH |
| salmeterol, fluticasone | -- | 170 UAH |
| salmeterol, fluticasone | 407 rub | -- |
| salmeterol, fluticasone propionate | -- | 83 UAH |
| salmeterol, fluticasone | -- | -- |
| salmeterol | 590 rub | -- |
| budesonide, formoterol | 799 rub | 263 UAH |
| budesonide, formoterol | 577 rub | -- |
| budesonide, formoterol | -- | -- |
| budesonide, formoterol fumarate dihydrate | 800 rub | -- |
| beclomethasone, formoterol | 1900 rub | 1900 UAH |
| mometasone, formoterol | 1257 rub | -- |
| vilanterol, fluticasone | 1563 rub | 1900 UAH |
| beclomethasone dipropionate, salbutamol | 730 rub | -- |
| fenoterol hydrobromide, ipratropium bromide | -- | -- |
| ipratropium bromide, fenoterol | 245 rub | 410 UAH |
| bromide, triphenate | 1909 rub | 502 UAH |
| glycopyrronium bromide, indacaterol | 2200 rub | -- |
| olodaterol, tiotropium bromide | 2395 rub | 710 UAH |
To compile a list of cheap analogues of expensive drugs, we use the prices provided by more than 10,000 pharmacies throughout Russia. The database of drugs and their analogues is updated daily, so the information provided on our website is always up-to-date as of the current day. If you have not found the analogue you are interested in, please use the search above and select the medicine you are interested in from the list. On the page of each of them you will find all possible options for analogues of the desired medicine, as well as prices and addresses of pharmacies in which it is available.
How to find a cheap analogue of an expensive medicine?
To find an inexpensive analogue of a drug, a generic or a synonym, we first of all recommend paying attention to the composition, namely, to the same active ingredients and indications for use. The same active ingredients of the drug will indicate that the drug is a synonym for the drug, a pharmaceutical equivalent or a pharmaceutical alternative. However, do not forget about the inactive components of similar drugs, which can affect safety and efficacy. Do not forget about the advice of doctors, self-medication can harm your health, so always consult a doctor before using any medication.Formoterol price
On the websites below you can find prices for Formoterol and find out about availability at a pharmacy nearbyFormoterol instruction
INSTRUCTIONS
for medical use of the drug
Formoterol
(Formoterol)
Pharmachologic effect:
Beta-adrenergic agent, stimulating mainly beta-adrenergic receptors. It has a bronchodilator (expanding the lumen of the bronchi) effect. Inhibits (suppresses) the release of histamine and leukotrienes (biologically active substances produced in the body) from the lung tissue. The onset of action of the drug after 5 minutes, maximum - after 2 hours, the duration of action with reversible bronchial obstruction (impaired air passage through the bronchi) 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 passage through them); bronchial asthma; bronchospasm caused by an allergen or exercise.
Mode of application:
The drug is administered by inhalation. For relief (removal) of acute bronchospasm, a single breath (12 μg) of the drug should be taken, if necessary, take a second breath in a minute. The maximum daily dose is 96 mcg (8 puffs). For the prevention of asthma attacks, 12 mcg (1 breath) is administered 2 times a day after 12 hours, in severe cases, 24 mcg 2 times a day at least 8 hours later.
Side effects:
Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (rapid heartbeat), nausea.
Contraindications:
Pregnancy, lactation, hypersensitivity 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. Do not combine formoterol with other adrenomimetic agents, MAO inhibitors, tricyclic antidepressants. With caution, the drug is prescribed to patients suffering from diabetes mellitus, with myoma (benign tumor of the muscular layer) of the uterus.
Release form:
Metered aerosol for inhalation in an inhaler of 100 doses. One dose contains 12 micrograms of formoterol fumarate.
Storage conditions:
List B. In a cool place, avoiding freezing. Protect from direct sunlight and heat sources.
Pharmacological group:
Medicines used to treat the bronchi and lungs
Anti-asthma medicines
Beta-adrenergic stimulants
Characteristics of the substance Formoterol
Bronchodilator (beta 2-agonist).
Available as formoterol fumarate and formoterol fumarate dihydrate. Formoterol fumarate is a white or yellowish crystalline powder. Easily soluble in glacial 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
pharmachologic effect- bronchodilator, adrenomimetic.Formoterol fumarate is a long-acting selective beta2 adrenergic agonist. When inhaled, formoterol fumarate acts locally on the bronchi, causing bronchodilation. In research in vitro it has been 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. In the myocardium, beta 2 -adrenergic receptors were also found, accounting 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 possibility of developing cardiac effects even with highly selective beta2-agonists. Formoterol fumarate stimulates intracellular adenylate cyclase, which catalyzes the transformation of ATP to cAMP. An increase in cAMP causes relaxation of bronchial smooth muscle and inhibits the release of immediate-type hypersensitivity mediators from cells, especially from mast cells. Research in vitro showed that formoterol fumarate inhibits the release of mediators (histamine and leukotrienes) from mast cells in the human lung. In animal studies, formoterol fumarate has been shown to inhibit histamine-induced plasma albumin extravasation in anesthetized guinea pigs and allergen-induced eosinophil influx in dogs with airway hyperreactivity. The significance of these facts obtained in animal studies and in vitro, is unclear to humans.
The main side effects of inhaled beta 2-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 convulsions, 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 micrograms of formoterol fumarate (10 times the recommended single dose). In all subjects, the content of potassium in the blood plasma decreased to the maximum by 0.55-1.52 mmol/l (the average maximum decrease was 1.01 mmol/l). A pronounced correlation was noted between the concentration of formoterol fumarate and the content of potassium in the blood plasma: the greatest effect on the level of potassium 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 amounted to 26 beats per minute. The maximum lengthening of the corrected QT interval (QTc) when calculated according to the Bazett formula averaged 25 milliseconds, 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 pulse rate and QTc increase. Effects on plasma potassium levels, pulse rate, QTc interval are known pharmacological effects of the drug class to which formoterol fumarate belongs, so their appearance in a study of very high doses of formoterol fumarate (120 mcg once, 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 those of albuterol (not registered in Russia) and placebo in two 12-week double-blind studies in patients with bronchial asthma; studies included long-term ECG monitoring over three 24-hour periods. There were no significant differences in ventricular or supraventricular ectopia between groups of patients (in two of these studies, the total number of patients with bronchial asthma who received any dose of formoterol fumarate and underwent continuous ECG monitoring was about 200 people). The effect of formoterol fumarate versus placebo on the ECG of patients with chronic obstructive pulmonary disease (COPD) was evaluated in a 12-month study (no long-term ECG monitoring was used). Analysis of ECG intervals was performed in patients who participated in studies in the United States; of these, 46 people took formoterol fumarate 12 mcg 2 times a day and 50 patients - 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 effects on ECG intervals, incl. QTc, in the treatment of formoterol fumarate was not detected. Formoterol fumarate, like other beta-agonists, can cause T wave smoothing, ST segment depression on the ECG; the clinical significance of these changes is unknown.
Tolerance. In clinical studies in 19 adult patients with moderate bronchial asthma, the bronchoprotective effect of formoterol fumarate was assessed by the response in the test with methacholine after taking an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks 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, the loss of protective properties was noted by the end of the 12-hour period after administration. There were no reactions of rebound bronchial hyperreactivity after the cessation of long-term therapy with formoterol fumarate.
Clinical researches
Studies in patients with bronchial asthma. In three large clinical trials in patients with bronchial asthma, while formoterol fumarate remained effective compared with placebo, there was a slight decrease in bronchodilatory response, assessed within 12 hours, while maintaining the effect of formoterol fumarate, especially when taken at 24 mcg twice a day ( twice the recommended daily dose).
In studies with single and multiple doses of formoterol fumarate at a dose of 12 mcg, the maximum improvement (indicators) in FEV 1 was usually noted between 1 and 3 hours after administration. An increase in FEV 1 compared with the initial value was detected within 12 hours after the use of the drug in most patients.
In 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), it was shown that formoterol fumarate ( 12 mcg twice a day) not only caused significant bronchodilation as measured by FEV 1 , but also improved many secondary efficacy indicators, including improvement according to the scales of symptoms of combined and nocturnal asthma, as well as a decrease in the number of nocturnal awakenings and nights when patients used drugs emergency care, an increase in morning and evening peak flow measurements (air flow rate).
Clinical studies in children. In a 12-month, multicenter, randomized, double-blind, parallel group study of patients treated with formoterol fumarate and placebo, 518 children aged 5-12 years with bronchial asthma, who required daily intake of bronchodilators and anti-inflammatory drugs, participated. 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 results of the study, the 12-hour efficacy of formoterol fumarate (according to the measured FEV 1) exceeded that of the placebo group at all indicated times.
Clinical studies on the efficacy of formoterol fumarate in exercise-induced bronchospasm(the effect was estimated as a decrease in FEV 1 by more than 20%). Four randomized, double-blind, comparative studies included 77 patients aged 4 to 41 years. Exercise response was assessed by FEV1 at 15 min, 4, 8, and 12 h after a single dose of 12 µg of formoterol fumarate and placebo. Scores in the formoterol fumarate group were significantly superior to those in the placebo group at all follow-up times. No study has been conducted on the efficacy of regular twice-daily use of formoterol in preventing exercise-induced asthma attacks.
Clinical studies in patients with COPD. In clinical trials with multiple doses of formoterol fumarate at a dose of 12 mcg in patients with COPD, marked bronchodilation (increase in FEV 1 by 15% or more) was noted 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 compared with pretreatment.
Pharmacokinetics
The pharmacokinetics of formoterol fumarate has been studied in healthy volunteers using higher than recommended doses and in patients with COPD receiving formoterol fumarate at therapeutic and higher doses. Urinary excretion of formoterol unchanged was used as an indirect indicator of systemic exposure. The distribution of formoterol from plasma corresponded to renal excretion, and T 1/2 distribution and excretion were similar. After a single inhalation in 12 healthy volunteers of 120 μg of formoterol fumarate, it was rapidly absorbed into 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 a day for 12 weeks, its average plasma concentration ranged from 4.0-8.8 pg / ml and 8.0-17.3 pg / ml, respectively, 10 minutes, 2 and 6 hours after inhalation. After inhalation of 12-96 µg of formoterol fumarate by 10 healthy volunteers, 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 in the considered dose range.
In a study in patients with bronchial asthma who received 12 and 24 mcg of formoterol fumarate by inhalation twice a day for 4 or 12 weeks, the cumulation index, assessed by excretion of unchanged drug in the urine, ranged from 1.63-2.08 compared with initial dose. For patients with COPD who used formoterol fumarate 12 and 24 mcg twice a day for 12 weeks, the cumulation index, calculated from the excretion of unchanged drug in the urine, was 1.19-1.38. This confirms some accumulation of formoterol fumarate in plasma with multiple doses. The amount of formoterol fumarate excreted against the background of the equilibrium concentration was almost equal to that predicted on the basis of pharmacokinetics after a single dose. Presumably, most of the formoterol fumarate (similar to other inhaled drugs) will be swallowed and then absorbed from the gastrointestinal tract. Binding in vitro with 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 that after inhalation of 120 mg of formoterol fumarate). Formoterol fumarate is metabolized primarily by direct glucuronidation at the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation 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). At therapeutic concentrations, formoterol does not inhibit cytochrome P450 enzymes. In some patients, there may be insufficient functional activity of one or both isoenzymes. CYP2D6 And CYP2C19. However, whether a deficiency of one or both isoenzymes can lead to an increase in systemic exposure or the development of systemic side effects is unknown (adequate studies have not been conducted). After ingestion of 80 micrograms of radiolabeled formoterol fumarate by two healthy volunteers, 59-62% was excreted in the urine and 32-34% in the faeces within 104 hours; their renal clearance of formoterol fumarate was about 150 ml/min. In 16 patients with bronchial asthma who received inhaled 12 micrograms or 24 micrograms of formoterol fumarate, 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 at the same doses, these figures were 7% and 6-9%, respectively. After a single inhalation of 120 μg of formoterol fumarate in 12 healthy volunteers, the terminal T 1/2 (based on measurements of plasma concentrations) was 10 hours. When calculated from the level of renal excretion, the terminal T 1/2 for R, R- and S, S-enantiomers of formoterol fumarate was 13.9 and 12.3 hours, respectively. After a single inhalation of 12-120 µg of formoterol fumarate in healthy volunteers, a single and repeated dose of formoterol fumarate at a dose of 12 µg or 24 µg in patients with bronchial asthma, the proportion of R, R- and S, S-enantiomers of the unchanged substance found in urine was 40% and 60%, respectively (the ratio of the two enantiomers remains constant over the studied dose range 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 given to elderly patients with bronchial asthma (318 people aged 65 years and over, 39 people aged 75 years and over) and COPD (395 and 62 people aged 65 years and over and 75 years and over, respectively) . There were no pronounced differences in the safety and efficacy of formoterol fumarate in elderly and younger people; respiratory tract infections with a slightly higher frequency were observed in patients aged 75 years and older, but their relationship with the intake of formoterol fumarate has not been established. In children aged 5-12 years with bronchial asthma who received inhaled formoterol fumarate at a dose of 12 mcg or 24 mcg twice a day for 12 weeks, the cumulation index calculated from the renal excretion of unchanged formoterol fumarate ranged from 1.18 to 1.84 (in adults - 1.63-2.08). In the urine of children, about 6% of formoterol fumarate was found unchanged and 6.5-9% in the form of conjugates. 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 have been noted with the simultaneous use of beta-agonists and methylxanthine derivatives. The clinical significance of these facts for humans has not been determined.
Carcinogenicity, mutagenicity, effect on fertility
The carcinogenicity study of formoterol fumarate was carried out in rats and mice treated with food or drinking water for 2 years. In rats, the incidence of ovarian leiomyoma increased at doses of formoterol fumarate of 15 mg/kg or more in drinking water and 20 mg/kg in food. When receiving 5 mg/kg of formoterol fumarate (an excess of about 450 times the AUC exposure in humans when taking inhaled MRDH) with food, the incidence of ovarian leiomyoma in rats did not increase. Cases of the development of benign theca-cell tumors of the ovaries 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 MRDH). These facts were not observed when formoterol fumarate was administered to rats with drinking water and in tests on mice. In male mice, cases of subcapsular adenomas and carcinomas of the adrenal glands increased when receiving 69 mg/kg or more of formoterol fumarate in drinking water; the development of these tumors was not noted when formoterol fumarate was taken with food at doses of about 50 mg / kg (AUC exposure is approximately 590 times higher than human exposure when inhaled with the maximum recommended daily dose). The development of hepatocarcinomas in mice was observed when taking with food 20 and 50 mg/kg of formoterol fumarate (females) and 50 mg/kg (males). The development of uterine leiomyomas and leiomyosarcomas was observed when taking formoterol fumarate with food at doses of 2 mg / kg or more (AUC exposure at a dose of 2 mg / kg is approximately 25 times higher than exposure in humans with inhalation administration of the maximum recommended daily dose). The increase in the incidence of leiomyomas of the organs of the reproductive system in female rodents was similar to the data of studies of other beta-adrenergic agonists.
Formoterol fumarate was not mutagenic or clastogenic in the following assays: bacterial and mammalian cell mutagenicity assay, mammalian cell chromosome assay, rat hepatocyte and human fibroblast DNA repair assay, mammalian fibroblast transformation assay, and micronucleus assays in mice and rats.
In a reproduction study in rats treated with formoterol fumarate orally at doses of about 3 mg/kg (approximately 1000 times the maximum recommended daily inhalation dose for humans on a body surface area basis in mg/m 2), no impaired 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 on a body surface area basis in mg/m 2 ) in late pregnancy, prenatal and neonatal mortality increased. These effects were not observed when taking 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 / m 2). Deceleration of ossification of the skeleton and a decrease in body weight were observed in the fetuses of rats that received formoterol fumarate during the period of organogenesis at the rate of 0.2 mg/kg and 6 mg/kg, respectively. In studies in rats and rabbits, formoterol fumarate did not cause malformations.
Application of the substance Formoterol
Based on Physician Desk Reference (2009), formoterol fumarate is indicated for long-term (twice a day - in the morning and evening) maintenance therapy for bronchial asthma and prevention (in adults and children 5 years 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 exercise-induced bronchospasm.
Formoterol fumarate is used for long-term (twice daily - morning and evening) maintenance therapy in patients with COPD, including chronic bronchitis and pulmonary emphysema.
Contraindications
Hypersensitivity.
Application restrictions
Cardiovascular disorders, incl. coronary insufficiency, arrhythmias, arterial hypertension, convulsive disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breastfeeding, age up to 5 years (safety and efficacy have not been established).
Formoterol fumarate is not recommended for patients who manage to control bronchial asthma 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 is fully adequate, one of which is an occasional inhaled short-acting beta 2 - adrenomimetic.
Use during pregnancy and lactation
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 (since beta-agonists can adversely affect uterine contractility) only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.
Formoterol fumarate is excreted in the milk of rats. It is not known whether it is excreted in breast milk in women, but because many drugs are excreted in human milk, formoterol fumarate should be administered with caution to lactating women (well-controlled studies in lactating women have not been conducted).
Side effects of the substance Formoterol
Side effects of formoterol fumarate are similar to those of other selective beta2-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
In controlled clinical trials, formoterol fumarate (12 mcg 2 times a day) was received by 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 of 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):
tremor 1.9% (0.4%), dizziness 1.6% (1.5%), insomnia 1.5% (0.8%).
bronchitis 4.6% (4.3%), chest infections 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 found to be dose-dependent (doses of 6, 12 and 24 mcg taken twice a day 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 bronchial asthma who needed daily bronchodilators and anti-inflammatory drugs. Against the background of 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. Adverse events in the formoterol fumarate group in children that were higher than those in the placebo group included infections/inflammation (viral infections, rhinitis, tonsillitis, gastroenteritis) or gastrointestinal complaints (abdominal pain, nausea, dyspepsia).
COPD
In two controlled studies, formoterol fumarate (12 mcg twice daily) was administered to 405 patients with COPD. The incidence of adverse events was comparable between the formoterol fumarate and placebo groups. Among the side effects in the formoterol fumarate group with a frequency equal to or greater than 1% and superior to that in the placebo group, the following were noted (next to the name is the percentage of occurrence in the formoterol fumarate group, in brackets - in the placebo group):
From the nervous system and sensory organs: seizures 1.7% (0%), calf muscle cramps 1.7% (0.5%), anxiety 1.5% (1.2%).
From the respiratory system: upper respiratory infections 7.4% (5.7%), pharyngitis 3.5% (2.4%), sinusitis 2.7% (1.7%), increased sputum 1.5% (1.2 %).
Others: back pain 4.2% (4.0%), chest pain 3.2% (2.1%), fever 2.2% (1.4%), pruritus 1.5% (1.0% ), dry mouth 1.2% (1.0%), injuries 1.2% (0%).
In general, the incidence of all cases of cardiovascular side effects in the two main studies was low and comparable with placebo (6.4% in patients taking 12 mcg of formoterol fumarate twice a day, and 6.0% in the placebo group). Specific cardiovascular side effects in the formoterol fumarate group, occurring at a frequency of 1% or more and exceeding the frequency of occurrence in the placebo group, were noted.
In two studies in patients taking 12 mcg and 24 mcg of formoterol fumarate twice daily, a dose-dependent pattern of seven side effects (pharyngitis, fever, convulsions, increased sputum count, dysphonia, myalgia and tremor) was noted.
Post-marketing research
During the extensive post-marketing use of formoterol fumarate, there have been reports of severe exacerbations of bronchial asthma, some of which ended fatally. Although most of these cases were noted in patients with severe bronchial asthma or acute decompensation of the condition, a few cases were noted in patients with less severe bronchial asthma. The relationship of these cases with the intake of formoterol fumarate has not been determined. There are rare reports of anaphylactic reactions, including severe hypotension and angioedema, associated with inhaled formoterol fumarate. Allergic reactions can manifest as urticaria and bronchospasm. Evidence of the development of drug dependence with the use of formoterol fumarate in clinical trials has not been received.
Interaction
Other adrenergic agents while taking formoterol should be used with caution, since there is a risk of potentiation of the predicted sympathomimetic effects of formoterol. With the simultaneous administration of xanthine derivatives, steroids or diuretics, the hypokalemic effect of adrenergic agonists may be enhanced. ECG changes and / or hypokalemia due to non-potassium-sparing diuretics, such as loop or thiazide diuretics, can be suddenly aggravated by beta-agonists, especially when the dose of the latter is exceeded (although the clinical significance of these effects is unclear, caution is required when prescribing drugs of these groups simultaneously ). Formoterol, like other beta 2-agonists, should be given with special attention while taking MAO inhibitors, tricyclic antidepressants or other drugs that can prolong the QTc interval, since this can potentiate the effect of adrenomimetics on the cardiovascular system (increased risk of developing ventricular arrhythmias ). Formoterol and beta-blockers can mutually suppress each other's effects when administered simultaneously. Beta-blockers can not only interfere with the pharmacological action of 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 bpm), arrhythmia, nervousness, headache, tremor, convulsive seizures, muscle cramps, dry mouth, palpitations, nausea, dizziness, fatigue, weakness, hypokalemia, hyperglycemia, insomnia, metabolic acidosis. Possible cardiac arrest and death (as with all inhaled sympathomimetics). The minimum lethal dose for rats treated with inhaled formoterol fumarate was 156 mg/kg (approximately 53,000 and 25,000 times the inhaled MRDH for adults and children, respectively, on a body surface area basis in mg/m2).
Treatment: withdrawal of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should be carried out taking into account the possible risk of developing bronchospasm. Data on the effectiveness of dialysis in overdose of formoterol fumarate are insufficient.
Routes of administration
Inhalation.
Precautions Substance Formoterol
Long-acting beta2-adrenergic agonists may increase the risk of death from asthma. Therefore, in the treatment of asthma, formoterol fumarate should only be used as an adjunct 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 medium 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 US placebo-controlled study 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 of death compared to placebo. These findings may also apply to formoterol fumarate, which is a long-acting beta2-adrenergic agonist.
Formoterol fumarate is not intended for the relief of an asthma attack. If, while taking formoterol fumarate at a previously effective dosage, attacks of bronchial asthma began to occur or the patient needs more than usual inhalations of short-acting beta 2-agonists, an urgent consultation with a doctor is necessary, since these are frequent signs of destabilization of the condition. 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. Do not increase the frequency of inhalations (more than 2 times a day). Formoterol fumarate should not be used in patients with apparent worsening or acute decompensation of asthma, as these may be 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 an alternative treatment instituted. 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 are no data on 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; stop taking or reduce the dose of corticosteroids should not be. Treatment with corticosteroids in patients previously taking these drugs by mouth or inhalation should be continued, even if the patient's condition improved as a result of taking formoterol fumarate. Any changes in the dose of corticosteroids, in particular reduction, should be based only on clinical assessment of the patient's condition.
Like other beta 2-adrenergic agonists, formoterol fumarate in some patients can cause clinically significant cardiovascular effects (increased heart rate, increased blood pressure, etc.); in such cases, formoterol fumarate should be discontinued. Like other beta2-agonists, formoterol can cause clinically significant hypokalemia (possibly due to intracellular redistribution of ions), which contributes to the development of adverse cardiovascular effects. Decreases in serum potassium are usually transient and do not require replacement.
In patients with bronchial asthma, the use of beta-blockers, incl. for secondary prevention of myocardial infarction, is undesirable. In such cases, the appointment of cardioselective beta-blockers should be considered, although they should be used with caution.
Characteristics of the substance FormoterolBronchodilator (beta2-agonist).
Available as formoterol fumarate and formoterol fumarate dihydrate. Formoterol fumarate is a white or yellowish crystalline powder. Easily soluble in glacial 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 - bronchodilating, adrenomimetic.
Formoterol fumarate is a long-acting selective beta2 adrenergic agonist. When inhaled, formoterol fumarate acts locally on the bronchi, causing bronchodilation. In vitro studies have shown that its activity against beta2-adrenergic receptors, located mainly in the smooth muscles of the bronchi, is more than 200 times higher than that against beta1-adrenergic receptors, located mainly in the myocardium. In the myocardium, beta2-adrenergic receptors were also found, accounting 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 possibility of developing cardiac effects even with highly selective beta2-adrenergic agonists. Formoterol fumarate stimulates intracellular adenylate cyclase, which catalyzes the transformation of ATP to cAMP. An increase in cAMP causes relaxation of bronchial smooth muscle and inhibits the release of immediate-type 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 has been shown to inhibit histamine-induced plasma albumin extravasation in anesthetized guinea pigs and allergen-induced eosinophil influx in dogs with airway hyperreactivity. The relevance of these findings from animal and in vitro studies to humans is unclear.
The main side effects of inhaled beta2-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 convulsions, insomnia, tachycardia, hypokalemia and hyperglycemia.
Application of the substance Formoterol
According to the Physician Desk Reference (2009), formoterol fumarate is indicated for long-term (twice daily - morning and evening) maintenance therapy in bronchial asthma and prevention (in adults and children 5 years and older) of bronchospasm in reversible obstructive airway diseases, including .h. 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 exercise-induced bronchospasm.
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.
Application restrictions
Cardiovascular disorders, incl. coronary insufficiency, arrhythmias, arterial hypertension, convulsive disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breastfeeding, age up to 5 years (safety and efficacy have not been established).
Formoterol fumarate is not recommended for patients who manage to control bronchial asthma only by non-systematic inhalation of short-acting beta2-adrenergic agonists, as well as for patients for whom therapy with inhaled corticosteroids or other drugs, one of which is an occasional inhaled short-acting beta2-adrenergic agonist, is fully adequate.
Use during pregnancy and lactation
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 (since beta-agonists can adversely affect uterine contractility) only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.
The FDA fetal category is C.
Formoterol fumarate is excreted in the milk of rats. It is not known whether it is excreted in breast milk in women, but because many drugs are excreted in human milk, formoterol fumarate should be administered with caution to lactating women (well-controlled studies in lactating women have not been conducted).
Side effects of the substance Formoterol
Side effects of formoterol fumarate are similar to those of other selective beta2-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
In controlled clinical trials, formoterol fumarate (12 mcg 2 times a day) was received by 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 of 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 nervous system and sensory organs: tremor 1.9% (0.4%), dizziness 1.6% (1.5%), insomnia 1.5% (0.8%).
From the respiratory system: bronchitis 4.6% (4.3%), chest infections 2.7% (0.4%), dyspnea 2.1% (1.7%), tonsillitis 1.2% ( 0.7%), dysphonia 1.0% (0.9%).
Other: 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 found to be dose-dependent (doses of 6, 12 and 24 mcg taken twice a day 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 bronchial asthma who needed daily bronchodilators and anti-inflammatory drugs. Against the background of 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. Adverse events in the formoterol fumarate group in children that were higher than those in the placebo group included infections/inflammation (viral infections, rhinitis, tonsillitis, gastroenteritis) or gastrointestinal complaints (abdominal pain, nausea, dyspepsia).
COPD
In two controlled studies, formoterol fumarate (12 mcg twice daily) was administered to 405 patients with COPD. The incidence of adverse events was comparable between the formoterol fumarate and placebo groups. Among the side effects in the formoterol fumarate group with a frequency equal to or greater than 1% and superior to that in the placebo group, the following were noted (next to the name is the percentage of occurrence in the formoterol fumarate group, in brackets - in the placebo group):
From the nervous system and sensory organs: convulsions 1.7% (0%), calf muscle cramps 1.7% (0.5%), anxiety 1.5% (1.2%).
From the respiratory system: infections of the upper respiratory tract 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%), pruritus 1.5% (1, 0%), dry mouth 1.2% (1.0%), injuries 1.2% (0%).
In general, the incidence of all cases of cardiovascular side effects in the two main studies was low and comparable with placebo (6.4% in patients taking 12 mcg of formoterol fumarate twice a day, and 6.0% in the placebo group). Specific cardiovascular side effects in the formoterol fumarate group, occurring at a frequency of 1% or more and exceeding the frequency of occurrence in the placebo group, were noted.
In two studies in patients taking 12 mcg and 24 mcg of formoterol fumarate twice daily, a dose-dependent pattern of seven side effects (pharyngitis, fever, convulsions, increased sputum count, dysphonia, myalgia and tremor) was noted.
Post-marketing research
During the extensive post-marketing use of formoterol fumarate, there have been reports of severe exacerbations of bronchial asthma, some of which ended fatally. Although most of these cases were noted in patients with severe bronchial asthma or acute decompensation of the condition, a few cases were noted in patients with less severe bronchial asthma. The relationship of these cases with the intake of formoterol fumarate has not been determined. There are rare reports of anaphylactic reactions, including severe hypotension and angioedema, associated with inhaled formoterol fumarate. Allergic reactions can manifest as urticaria and bronchospasm. Evidence of the development of drug dependence with the use of formoterol fumarate in clinical trials has not been received.
Interaction
Other adrenergic agents while taking formoterol should be used with caution, since there is a risk of potentiation of the predicted sympathomimetic effects of formoterol. With the simultaneous administration of xanthine derivatives, steroids or diuretics, the hypokalemic effect of adrenergic agonists may be enhanced. ECG changes and / or hypokalemia due to non-potassium-sparing diuretics, such as loop or thiazide diuretics, can be suddenly aggravated by beta-agonists, especially when the dose of the latter is exceeded (although the clinical significance of these effects is unclear, caution is required when prescribing drugs of these groups simultaneously ). Formoterol, like other beta2-agonists, should be given with special attention while taking MAO inhibitors, tricyclic antidepressants or other drugs that can prolong the QTc interval, since this can potentiate the effect of adrenomimetics on the cardiovascular system (increased risk of developing ventricular arrhythmias) . Formoterol and beta-blockers can mutually suppress each other's effects when administered simultaneously. Beta-blockers can not only interfere with the pharmacological action of 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 bpm), arrhythmia, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitations, nausea, dizziness, fatigue, weakness, hypokalemia, hyperglycemia, insomnia, metabolic acidosis. Possible cardiac arrest and death (as with all inhaled sympathomimetics). The minimum lethal dose for rats treated with inhaled formoterol fumarate was 156 mg/kg (approximately 53,000 and 25,000 times the inhaled MRDH for adults and children, respectively, on a body surface area basis in mg/m2).
Treatment: withdrawal of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should be carried out taking into account the possible risk of developing bronchospasm. Data on the effectiveness of dialysis in overdose of formoterol fumarate are insufficient.
Routes of administration
Inhalation.
Precautions Substance Formoterol
Long-acting beta2-adrenergic agonists may increase the risk of death from asthma. Therefore, in the treatment of asthma, formoterol fumarate should only be used as an adjunct 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 medium 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 US placebo-controlled study 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 of death compared with placebo. These findings may extend to formoterol fumarate, which is a long-acting beta2-adrenergic agonist.
Formoterol fumarate is not intended for the relief of an asthma attack. If, while taking formoterol fumarate at a previously effective dosage, attacks of bronchial asthma began to occur or the patient needs more inhalations of short-acting beta2-agonists than usual, an urgent consultation with a doctor is necessary, since these are frequent signs of destabilization of the condition. 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. Do not increase the frequency of inhalations (more than 2 times a day). Formoterol fumarate should not be used in patients with apparent worsening or acute decompensation of asthma, as these may be life-threatening situations.
Like other inhaled beta2-agonists, formoterol fumarate can cause paradoxical bronchospasm; in this case, formoterol fumarate should be stopped immediately and an alternative treatment instituted. In many patients, monotherapy with beta2-agonists does not provide adequate control of asthma symptoms; such patients require early administration of anti-inflammatory drugs, such as corticosteroids.
There are no data on 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; stop taking or reduce the dose of corticosteroids should not be. Treatment with corticosteroids in patients previously taking these drugs by mouth or inhalation should be continued, even if the patient's condition improved as a result of taking formoterol fumarate. Any changes in the dose of corticosteroids, in particular reduction, should be based only on clinical assessment of the patient's condition.
Like other beta2-adrenergic agonists, formoterol fumarate in some patients can cause clinically significant cardiovascular effects (increased heart rate, increased blood pressure, etc.); in such cases, formoterol fumarate should be discontinued. Similar to other beta2-agonists, formoterol can cause clinically significant hypokalemia (possibly due to intracellular redistribution of ions), which contributes to the development of adverse cardiovascular effects. Decreases in serum potassium are usually transient and do not require replacement.
In patients with bronchial asthma, the use of beta-blockers, incl. for secondary prevention of myocardial infarction, is undesirable. In such cases, the appointment of cardioselective beta-blockers should be considered, although they should be used with caution.
special instructions
Capsules containing formoterol fumarate should not be taken orally; they should only be used by inhalation through a special device. Do not exhale into the inhalation device.
Name: Formoterol (Formoterol)
Pharmacological effect:
Beta-adrenergic agent, stimulating mainly beta-adrenergic receptors. It has a bronchodilator (expanding the lumen of the bronchi) effect. Inhibits (suppresses) the release of histamine and leukotrienes (biologically active substances produced in the body) from the lung tissue. The onset of action of the drug is after 5 minutes, maximum - after 2 hours, the duration of action with reversible bronchial obstruction (impaired air passage through the bronchi) is up to 10 hours.
Formoterol - 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 passage through them); bronchial asthma; bronchospasm caused by an allergen or exercise.Formoterol - method of application:
The drug is administered by inhalation. For relief (removal) of acute bronchospasm, a single breath (12 mcg) of the drug should be taken, if necessary, take a second breath in a minute. The highest daily dosage is 96 mcg (8 puffs). To prevent asthma attacks, 12 mcg (1 breath) is administered 2 times a day after 12 hours, in severe cases, 24 mcg 2 times a day at least 8 hours later.Formoterol - side effects:
Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (rapid heartbeat), nausea.Formoterol - contraindications:
Pregnancy, lactation, hypersensitivity to the drug or beta-agonists.When using the drug, patients are not encouraged to engage in activities that require increased attention or coordination of movements. It is not necessary to combine formoterol with other adrenomimetic agents, MAO inhibitors, tricyclic antidepressants. With caution, the drug is prescribed to patients suffering from diabetes mellitus, with myoma (benign tumor of the muscular layer) of the uterus.
Formoterol - release form:
Metered aerosol for inhalation in an inhaler of 100 doses. One dosage contains 12 micrograms of formoterol fumarate.Formoterol - storage conditions:
List B. In a cool place, avoiding freezing. Protect from direct sunlight and heat sources.Formoterol - synonyms:
Foradil.Important!
Before using the medicine Formoterol you should consult your doctor. This manual is for informational purposes only.
