Atimos, Oxisturbuhaler, Foradil.
Composition and release form
Formoterol fumarate.
Capsules complete with aerolizer (12 mcg); Formoterol fumarate microionized. Metered aerosol for inhalation (1 dose - 12 mcg); dosed powder for inhalation (1 dose - 4.5 mcg, 9 mcg).
Formoterol fumarate dihydrate.
Capsules with powder for inhalation (12 mcg).
pharmachologic effect
Beta adrenergic agonist. Acts primarily on beta2-adrenergic receptors. It has a bronchodilator effect, relieves and prevents bronchospasm. Inhibits the release of histamine, leukotrienes and prostaglandin D2 from mast cells, basophilic granulocytes and sensitized cells of the bronchoalveolar tree.
Pharmacokinetics
It is expected that after inhalation, most of the fumarate will be swallowed and then absorbed from the gastrointestinal tract. Binding to blood plasma proteins (albumin) - 31-38%. T1/2 of various metabolites - 13.9 and 12.3 hours. Metabolized in the liver. It is excreted in the urine unchanged and in the form of metabolites.
Indications
Prevention and treatment of bronchospasm in patients with obstructive .
Application
The drug is administered by inhalation. To relieve acute bronchospasm, you should take a single inhalation (12 mcg) of the drug, and, if necessary, inhale again after 1 minute. If the therapeutic effect is weak, you can take 2 more breaths after 30 minutes. The maximum daily dose is 96 mcg (8 breaths).
To prevent asthma attacks, take one breath (12 mcg) in the morning and evening, and in severe cases, take two breaths (24 mcg) 2 times a day. The interval between administrations should be at least 8 hours.
The drug is prescribed with caution to patients suffering from diabetes mellitus, as well as uterine fibroids. When using the drug, patients are not recommended to engage in potentially hazardous activities that require increased attention and rapid mental and motor reactions. The use of the aerosol in young children should only be carried out under the supervision of adults.
Side effect
Headache, nausea, dizziness, dry mouth, nervousness, tremor, convulsions, tachycardia and tachyarrhythmia.
Contraindications
Hypersensitivity to the drug or other beta-agonists, thyrotoxicosis, tachyarrhythmias, pregnancy and lactation.
73573-87-2Characteristics of the substance Formoterol
Bronchodilator (beta 2 adrenergic agonist).
Available in the form of 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 adrenergic beta 2 receptor 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 adrenoreceptors, located mainly in the smooth muscles of the bronchi, is more than 200 times higher than that against beta 1 adrenoreceptors, 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. 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 was found to inhibit histamine-induced plasma albumin extravasation in anesthetized guinea pigs and allergen-induced eosinophil influx in dogs with airway hyperresponsiveness. The significance of these facts obtained from animal studies and in vitro, unclear to 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: the greatest effect on potassium levels was observed 1-3 hours after the Cmax of formoterol fumarate was reached. 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, and 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 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 effects on 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; the clinical significance of these changes is unknown.
Tolerance. In a clinical study on 19 adult patients with moderate bronchial asthma, the bronchoprotective effect of formoterol fumarate was assessed by the response in a methacholine test 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, loss of protective properties was noted by 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 large clinical trials in patients with asthma, while the effectiveness of formoterol fumarate compared with placebo was maintained, there was a slight decrease in the bronchodilator response assessed over 12 hours, while the effect of formoterol fumarate was maintained, 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, increasing morning and evening peak flow measurements (air flow rate).
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 in patients with COPD, pronounced bronchodilation was noted (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 higher than recommended, 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 average 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 a day 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. 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 those after inhalation of 120 mg of 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). At therapeutic concentrations, formoterol does not inhibit cytochrome P450 enzymes. Some patients may experience insufficient functional activity of one or both isoenzymes CYP2D6 And CYP2C19. However, whether deficiency of one or both isoenzymes may lead to increased systemic exposure or the development of systemic side effects is 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 by 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) . There were no significant differences in the safety and effectiveness of formoterol fumarate in elderly and younger people; 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 daily for 12 weeks, the accumulation index, calculated from the renal excretion of unchanged formoterol fumarate, ranged from 1.18-1.84 (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 were reported 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
A study of the carcinogenicity of formoterol fumarate was carried out on rats and mice receiving it for 2 years through 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). The increase in the incidence of leiomyomas of the 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 studies on bacterial and mammalian cells, chromosomal analysis on mammalian cells, DNA repair studies on rat hepatocytes and human fibroblasts, mammalian fibroblast transformation assays, 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. Rats treated with formoterol fumarate at a dose of 6 mg/kg (2000 times the maximum recommended daily human inhalation dose based on body surface area in mg/m2) during late pregnancy had increased prenatal and neonatal mortality. 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.
Use of the substance Formoterol
According to 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 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, convulsive disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breastfeeding, age under 5 years (safety and effectiveness have not been established).
Formoterol fumarate is not recommended for patients whose 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 is completely adequate, one of which is an inhaled short-acting beta 2-adrenergic agonist from time to time. 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 nursing women).
Side effects of the substance Formoterol
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 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 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 that exceeded the incidence of side effects in the placebo group included infections/inflammation (viral infections, rhinitis, tonsillitis, gastroenteritis) or gastrointestinal complaints (abdominal pain, nausea, dyspepsia).
COPD
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: cramps 1.7% (0%), calf muscle cramps 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 %).
Others: 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%), injuries 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 hypotension and angioedema, associated with inhaled formoterol fumarate. Allergic reactions can manifest themselves in the form of 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. When taking xanthine derivatives, steroids or diuretics simultaneously, the hypokalemic effect of adrenergic receptor agonists may be enhanced. 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-administering drugs of these groups ). Formoterol, like other beta 2-agonists, should be prescribed with special attention when taking MAO inhibitors, tricyclic antidepressants or other drugs that can prolong the QTc interval, as this may potentiate the effect of adrenergic agonists on the 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 antagonize the pharmacological action of beta agonists, but may also cause severe bronchospasm in patients with asthma.
Overdose
Symptoms: angina pectoris, 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 by 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: withdrawal of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should take into account the possible risk of bronchospasm. Data on the effectiveness of dialysis for formoterol fumarate overdose are insufficient.
Routes of administration
Inhalation.
Precautions for the substance Formoterol
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 beta 2 -adrenergic agonist (salmeterol) with placebo when added to conventional asthma therapy showed that salmeterol resulted in an increased risk of death compared with 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 at a previously effective dosage, attacks of bronchial asthma begin to occur or the patient requires a greater than usual number of inhalations of short-acting beta 2 agonists, 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. 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 be a life-threatening situation.
Like other inhaled beta 2 -agonists, formoterol fumarate can cause paradoxical bronchospasm; in this case, formoterol fumarate should be discontinued immediately and alternative treatment should be prescribed. 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 of myocardial infarction, is undesirable. In such cases, the use of cardioselective beta-blockers should be considered, although they should be used with caution.
Composition and release form of the drug
Capsules with powder for inhalation solid transparent, size No. 3, light brown; the contents of the capsules are white or almost white powder.
Excipients: sodium benzoate - 0.02 mg, lactose monohydrate - up to 12 mg.
Composition of the capsule shell: caramel coloring (E150c) - 1.4388%, hypromellose - up to 100%.
10 pieces. - contour cell packaging (3) included. with a device for inhalation. or without it - cardboard packs.
10 pieces. - contour cell packaging (6) included. with a device for inhalation. or without it - cardboard packs.
pharmachologic effect
Beta adrenergic agonist. Acts primarily on β 2 -adrenergic receptors. It has a bronchodilator effect, relieves and prevents bronchospasm. Inhibits the release of histamine, leukotrienes and prostaglandin D 2 from mast cells, basophils and sensitized cells of the bronchoalveolar tree.
Pharmacokinetics
When administered by inhalation, about 90% of the active substance can be swallowed. When taken orally, it is quickly absorbed from the gastrointestinal tract. Absorption is 65%. Cmax is reached within 0.5-1 hour. Plasma protein binding is 61-64%. T 1/2 - 2-3 hours. Metabolized mainly by glucuronidation. Excreted by the kidneys (70%) and through the intestines (30%). Renal clearance – 150 ml/min.
When used by inhalation, it is quickly absorbed, C max is reached after 15 minutes, the concentration of the active substance in the lungs after inhalation with a turbuhaler is 21-37%. Bioavailability – 46%. Protein binding 50%. T 1/2 – 8 hours.
Indications
Prevention and treatment of bronchospasm in patients with obstructive bronchitis and bronchial asthma.
Contraindications
Hypersensitivity to formoterol or other beta-agonists, children under 5 years of age.
Dosage
Used in the form of inhalations. The dose depends on the dosage form used and the age of the patient.
Side effects
Maybe:, nausea, dry mouth, tremor.
Rarely: muscle cramps, myalgia, tachycardia, dizziness, agitation, anxiety, sleep disturbances, nervousness, increased bronchospasm.
In some cases: hypersensitivity reactions (severe arterial hypotension, urticaria, angioedema, itching, exanthema), peripheral edema, changes in taste.
Drug interactions
You should not combine formoterol with adrenomimetic drugs, MAO inhibitors, tricyclic antidepressants (the risk of side effects from the cardiovascular system increases).
With simultaneous use, xanthine derivatives, corticosteroids, and diuretics increase the likelihood of a hypokalemic effect of the drug.
With simultaneous use of quinidine, disopyramide, procainamide, phenothiazines, antihistamines, tricyclic antidepressants, they increase the risk of developing ventricular arrhythmias.
(including in the form of eye drops) partially or completely block the effect of formoterol.
special instructions
Particular caution and close monitoring are required if it is necessary to use formoterol in patients with the following concomitant diseases: coronary artery disease; rhythm and conduction disturbances, especially third degree AV block; severe heart failure; idiopathic subvalvular aortic stenosis; hypertrophic obstructive cardiomyopathy; thyrotoxicosis; known or suspected prolongation of the QT interval (QT corrected >0.44 sec).
Use with caution in patients with diabetes mellitus and uterine fibroids.
Impact on the ability to drive vehicles and operate machinery
Tremor or anxiety that occurs during treatment with beta-agonists may affect the patient's ability to drive, therefore, when using formoterol, it is not recommended to engage in potentially hazardous activities that require increased attention and rapid psychomotor reactions.
Pregnancy and lactation
During and during lactation, formoterol is used with caution, only in cases where the expected therapeutic effect for the mother outweighs the potential risk of side effects for the fetus or child.
Name: Formoterol
Pharmacological effects:
Beta-adrenomimetic agent, stimulating mainly 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 medicine 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.
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 flow through them); bronchial asthma; bronchospasm caused by an allergen or physical activity.Formoterol - method of application:
The drug is administered by inhalation. To relieve (relieve) acute bronchospasm, take a single inhalation (12 mcg) of the medication, and, if necessary, inhale again after a minute. The highest daily dosage is 96 mcg (8 breaths). To prevent asthma attacks, administer 12 mcg (1 breath) 2 times a day after 12 hours, in severe cases - 24 mcg 2 times a day at least after 8 hours.Formoterol - side effects:
Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (rapid heartbeat), nausea.Formoterol - contraindications:
Pregnancy, breastfeeding, hypersensitivity to the drug or beta-agonists.When using the medicine, patients are not asked 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.
Formoterol - release form:
Metered aerosol for inhalation in an inhaler, 100 doses. One dose contains 12 mcg of formoterol fumarate.Formoterol - storage conditions:
List B. In a cool place, avoid freezing. Protect from direct sunlight and heat sources.Formoterol - synonyms:
Foradil.Important!
Before using the medicine Formoterol you should consult your doctor. This instruction is intended for informational purposes only.
Name:
Formoterol
Pharmachologic effect:
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.
Method 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. The maximum daily dose is 96 mcg (8 puffs). To prevent asthma attacks, administer 12 mcg (1 breath) 2 times a day after 12 hours, in severe cases - 24 mcg 2 times a day at least after 8 hours.
Adverse events:
Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (rapid heartbeat), nausea.
Contraindications:
Pregnancy, breastfeeding, 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. 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 of the drug:
Metered aerosol for inhalation in an inhaler, 100 doses. One dose contains 12 mcg of formoterol fumarate.
Storage conditions:
A drug from list B. In a cool place, avoid freezing. Protect from direct sunlight and heat sources.
Synonyms:
Foradil.
Drugs with similar effects:
Bronchoryl Theo-Asthalin forte Theo-Asthalin Isadrinum Gambaran
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